JP6486887B2 - Anti-IL-6 receptor antibody administered subcutaneously - Google Patents

Description

(Related application)
This application claims the benefit of US provisional application 61 / 411,015 filed on November 8, 2010 and US provisional application 61 / 542,615 filed on October 3, 2011. And is incorporated by reference in its entirety.

(Field of Invention)
The present application is an antibody administered subcutaneously that binds the interleukin 6 receptor (anti-IL-6R antibody), and includes rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), systemic JIA (sJIA), polyarticular It relates to a method for treating IL-6 mediated diseases such as type JIA (pcJIA), systemic sclerosis or giant cell arteritis (GCA). The application particularly relates to the determination of a fixed dose of an anti-IL-6R antibody, such as tocilizumab, that is safe and effective for subcutaneous administration to patients with IL-6 mediated diseases. In addition, formulations and devices useful for subcutaneous administration of anti-IL-6R antibodies are disclosed.

  Rheumatoid arthritis is a progressive systemic autoimmune disease characterized by synovitis that destroys movable joints and is accompanied by fatigue, anemia and osteopenia. The prevalence of rheumatoid arthritis ranges from 0.5% to 1.0% (Maddison PJ, Isenberg DA, Woo P, Glass DN, Oxford Textbook of Rheumatology: Oxford University Press: 499-513 (1993) Silman, AJ “Epidemiology and the rheumatic diseases.”), Peak incidence is between 40 and 60 years, mainly in women. The cause of RA is unknown, but certain histocompatibility antigens have been associated with poor outcome. Non-steroidal anti-inflammatory drugs (NSAIDs) only provide symptom relief. Disease-modifying anti-rheumatic drugs (DMARDs) are the basis of treatment in all stages of RA (Maddison et al., Supra) and maintain or improve physical function and delay joint destruction by X-rays (Brooks, PM “Clinical Management of rheumatoid arthritis. ”Lancet 341: 286-290 (1993)). Recently, biological compounds targeting tumor necrosis factor alpha (TNF-α), B cells or T cells have been used successfully in RA treatment, but about 30% to 40% of patients are in these treatments. Does not respond (Bathon et al. New Eng. J. Med. 343: 1586-1592 (2000); Maini et al. Arthritis & Rheumatism 41: 1552-1563 (1998)).

  Interleukin 6 (IL-6) is a pro-inflammatory multifunctional cytokine produced by various cell types. IL-6 activates T cells, differentiates B cells, induces acute phase proteins, stimulates growth and differentiation of hematopoietic progenitor cells, promotes osteoclast differentiation from progenitor cells, stem cells / skin cells / neuronal cells It is involved in various processes such as proliferation, bone metabolism and lipid metabolism (Hirano T. Chem Immunol. 51: 153-180 (1992); Keller et al. Frontiers Biosci. 1: 340-357 (1996); Metzger et al. Am J Physiol Endocrinol Metab. 281: E597-E965 (2001); Tamura et al. Proc Natl Acad Sci USA. 90: 11924-11928 (1993); Taub R. J Clin Invest 112: 978-980 (2003)). IL-6 has been implicated in the pathogenesis of various diseases including autoimmune diseases, osteoporosis, neoplasms and aging (Hirano, T. (1992), supra; and Keller et al., Supra). IL-6 affects through a ligand-specific receptor (IL-6R) that exists in both soluble and membrane-expressed forms.

  High concentrations of IL-6 in the serum and synovial fluid of RA patients have been reported, indicating that IL-6 is produced by the synovium (Irano et al. Eur J Immunol. 18: 1797-1801 ( 1988); and Houssiau et al. Arthritis Rheum. 1988; 31: 784-788 (1988)). IL-6 concentration correlates with disease activity of RA (Hirano et al. (1988), supra) and clinical effects are accompanied by a decrease in serum IL-6 concentration (Madhok et al. Arthritis Rheum. 33: S154. Abstract (1990) ).

  Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody of a subclass of immunoglobulin IgG1 that binds human IL-6R. Roche and Chugai completed the clinical efficacy and safety study of intravenous (IV) TCZ in various disease areas including adult-onset RA, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis, Or it has been implemented.

  TCZ 8 mg / kg IV is approved for use in RA in more than 70 countries including Japan and Europe. In the United States, TCZ IV (4 mg / kg and 8 mg / kg) is approved for use in RA patients with poor response to anti-TNF agents. In addition, India and Japan have approved the use of TCZ for Castleman's disease.

  On April 15, 2011, the US Food and Drug Administration approved TCZ alone or in combination with methotrexate for the treatment of active systemic juvenile idiopathic arthritis (sJIA) (TCZ ACTEMRA® US (Attachment (USPI), April 2011). On August 1, 2011, TCZ was approved in the EU for the treatment of active sJIA with a poor response to past treatment with NSAIDs and systemic corticosteroids (CS). Can be administered to patients over 2 years of age (intolerant tolerance to MTX and inadequate MTX therapy) or in combination with MTX (RoACTEMRA Product Characteristics Summary (SmPC), Roche Registration Limited, 6 Falcon Way Shire Park , Welwyn Garden City, AL7 1TW, United Kingdom, June 4, 2010). The approved TCZ dose for sJIA patients is 12 mg / kg TCZ for body weight <30 kg, 8 mg / kg IV infusion every 2 weeks for patients with body weight ≧ 30 kg.

  TCZ is approved in Japan for the treatment of polyarticular juvenile idiopathic arthritis (pcJIA) based on a phase III study MRA318JP conducted in Japanese patients. WA 19977 is examining the efficacy, safety, PK and PD of TCZ in pcJIA patients aged 2 to 17 years in an ongoing pivotal phase 3 study.

  TCZ is found in 2 Japanese patients with diffuse cutaneous systemic sclerosis (SSc) (Shima et al. Rheumatology 49: 2408-12 (2010), doi: 10.1093 / rheumatology / keq275) and 5 SSc patients (Meunier et al. Ann. Rheum. Dis. 70 (Suppl 3): 660 (2011)). High concentrations of circulating IL-6 have been reported in SSc patients, particularly early patients. IL-6 is overexpressed in endothelial cells and fibroblasts in lesional skin of SSc patients (Koch et al. Pathobiology 61: 239-46 (1993)). High concentrations of IL-6 have been detected in lavage of bronchoalveolar epithelium of SSc patients. It has been reported that skin fibroblasts of SSc patients express constitutively high levels of IL-6 as compared to healthy groups (Kadono et al. J. Rheumatol. 25: 296-301 (1998)). In addition, serum IL-6 concentrations are positively correlated with scleroderma and acute phase proteins (Ong and Denton, Curr. Opin. Rheumatol. 22: 264-72 (2010)).

  IL-6 was originally described as a potential growth and maturation factor that generates human plasma cells. IL-6 induces B cell proliferation, antibody secretion and plasmablast survival. Active B cells produce IL-6 and other cytokines. In SSc patients, activation of polyclonal B cells, the presence of highly specific autoantibodies, infiltration of B lymphocytes in the patient's skin disease area, etc. have been observed. However, the results of an open-label study of B cell-depleting antibodies in SSc patients are uncertain to date (Bosello et al. Arthritis Res. Therapy 12: R54 (2010); Layfatis et al. Arthritis Rheum. 60; 578-83 (2009) Daoussis et al. Rheumatology 49: 271-80 (2010)). Bosello et al. (2010) reported the beneficial effects of B cell depletion in SSc patients associated with decreased serum IL-6 levels. In addition to its effect on B cell function, IL-6 also has a specific effect on T cells. IL-6 promotes T cell survival and Th17 lymphocyte differentiation and inhibits the development of regulatory T cells. Th17 cells produce IL-17 and have been linked to the development of autoimmune diseases. In the autocrine loop, IL-17 can induce IL-6 synthesis in human fibroblasts (Fossiez et al. J. Exp. Med. 813: 2593-2603 (1996)). Although an increase in circulating Th17 cells has recently been reported in patients with SSc (Radstake et al. PLoS ONE 4 (6): e5903. Doi: 10.1371 / journal.pone.0005903. Atamas SP Life Sci 72: 631-43 (2009)) It has been discovered that IL-17 levels in serum and bronchial epithelial lavage fluid are increased in SSc and ILD patients (Kurasawa et al. Arthritis Rheum 43: 2455-63 (2000)).

  The inflammatory phase of SSc gradually changes to fibrosis. In vitro human skin fibroblast culture experiments showed that IL-6 increased production of type I collagen, glycosaminoglycan, hyaluronic acid and chondroitin sulfate (Duncan and Berman J. Invest. Dermatol. 97: 686-92 (1991)).

  Giant cell arteritis (GCA) is primary vasculitis of large or medium diameter arteries, typically diagnosed by temporal artery biopsy. Signs and symptoms of GCA include high erythrocyte sedimentation rate (ESR) or new headache. Adverse sequelae include irreversible blindness (bilateral retinal or optic nerve ischemia), brain, lower limb, upper limb or aortic aneurysm infarction. GCA is an unmet medical need. High-dose corticosteroids (CS) are the current standard treatment, but a more durable remission is needed (50% of patients relapse), saving steroids in terms of steroid-related complications Therapy options are needed. Case studies reporting TCZ use in giant cell arteritis include Seitz et al. Swiss Med Wkly 141: w13156 pgs. E1-E4 (2011); Salvarani et al. Arth. And Rheum. (April 2011); and Beyer et al. Ann. Rheum. Dis. Pgs. 1-2 (2011), doi: 10.1136 / ard.2010.149351. In all studies, TCA was administered intravenously.

  Patents and patent publications related to anti-IL-6 antibodies include: US Pat. No. 5,171,840 (Kishimoto), US Pat. No. 5,480,796 (Kishimoto), US Pat. No. 5,670,373 (Kishimoto), US Pat. 5,851,793 (Kishimoto), U.S. Patent No. 5,990,282 (Kishimoto), U.S. Patent No. 6,410,691 (Kishimoto), U.S. Patent No. 6,428,979 (Kishimoto), U.S. Patent No. 5,795,965 (Tsuchiya et al.), U.S. Patent No. 5,817,790 (Tsuchiya) U.S. Patent No. 7,479,543 (Tsuchiya et al.), U.S. Patent Publication No. 2005/0142635 (Tsuchiya et al.), U.S. Patent No. 5,888,510 (Kishimoto et al.), U.S. Patent Publication No. 2001/0001663 (Kishimoto et al.), United States Patent Publication No. 2007/0036785 (Kishimoto et al.), U.S. Patent No. 6,086,874 (Yoshida et al.), U.S. Patent No. 6,261,560 (Tsujinaka et al.), U.S. Patent No. 6,692,742 (Nakamura et al.), U.S. Patent No. 7,566,453 (Nakamura et al.) ), U.S. Patent No. 7,771,723 (Nakamura et al.), U.S. Patent Publication No. 2002/0131967 (Nakamura et al.), U.S. Patent Publication No. 200 No. 4/0247621 (Nakamura et al.), U.S. Patent Publication No. 2002/0187150 (Mihara et al.), U.S. Patent Publication No. 2005/0238644 (Mihara et al.), U.S. Patent Publication No. 2009/0022719 (Mihara et al.), U.S. Patents Publication No. 2006/0134113 (Mihara), U.S. Patent No. 6,723,319 (Ito et al.), U.S. Patent No. 7,824,674 (Ito et al.), U.S. Patent Publication No. 2004/0071706 (Ito et al.), U.S. Patent No. 6,537,782 (Shibuya U.S. Patent No. 6,962,812 (Shibuya et al.), International Publication No. 00/10607 (Akihiro et al.), U.S. Patent Publication No. 2003/0190316 (Kakuta et al.), U.S. Patent Publication No. 2003/0096372 (Shibuya et al.) , U.S. Patent No. 7,320,792 (Ito et al.), U.S. Patent Publication No. 2008/0124325 (Ito et al.), U.S. Patent Publication No. 2004/0028681 (Ito et al.), U.S. Patent Publication No. 2008/0124325 (Ito et al.), US Patent Publication No. 2006/0292147 (Yoshizaki et al.), US Patent Publication No. 2007/0243189 (Yoshizaki et al.), US Patent Publication No. 2004/0115197 (Yoshizaki et al.), US Patent Publication No. 2007/0148169 (Yoshizaki et al.) ), U.S. Pat.No. 7,332,289 (Takeda U.S. Patent No. 7,927,815 (Takeda et al.), U.S. Patent No. 7,955,598 (Yoshizaki et al.), U.S. Patent Publication No. 2004/0138424 (Takeda et al.), U.S. Patent Publication No. 2008/0255342 (Takeda et al.), U.S. Pat. Patent Publication No. 2005/0118163 (Mizushima et al.), United States Patent Publication No. 2005/0214278 (Kakuta et al.), United States Patent Publication No. 2008/0306247 (Mizushima et al.), United States Patent Publication No. 2009/0131639 (Kakuta et al.) U.S. Patent Publication No. 2006/0142549 (Takeda et al.), U.S. Patent No. 7,521,052 (Okuda et al.), U.S. Patent Publication No. 2009/0181029 (Okuda et al.), U.S. Patent Publication No. 2006/0251653 (Okuda et al.), US Patent Publication No. 2009/0181029 (Okuda et al.), US Patent Publication No. 2007/0134242 (Nishimoto et al.), US Patent Publication No. 2008/0274106 (Nishimoto et al.), US Patent Publication No. 2007/0098714 (Nishimoto et al.) ), U.S. Patent Publication No. 2010/0247523 (Kano et al.), U.S. Patent Publication No. 2006/0165696 (Okano et al.), U.S. Patent Publication No. 2008/0124761 (Goto et al.), U.S. Patent Publication No. 2009/0220499 ( Yasunami), US patent No. 2009/0220500 (Kobara), U.S. Patent Publication No. 2009/0263384 (Okada et al.), U.S. Patent Publication No. 2009/0291076 (Morichika et al.), U.S. Patent Publication No. 2009/0269335 (Nakashima et al.), United States Patent Publication No. 2010/0034811 (Ishida), United States Patent Publication No. 2010/0008907 (Nishimoto et al.), United States Patent Publication No. 2010/0061986 (Takahashi et al.), United States Patent Publication No. 2010/0129355 (Ohguro et al.), US Patent Publication No. 2010/0255007 (Mihara et al.), US Patent Publication No. 2010/0304400 (Stubenrach et al.), US Patent Publication No. 2010/0285011 (Imaeda et al.), US Patent Publication No. 2011/0150869 (Mitsunaga et al.) ), International Publication No. 2011/013786 (Maeda), and US Patent Publication No. 2011/0117087 (Franze et al.).

  In a first aspect, the present invention provides a method of treating an IL-6 mediated disease in a patient comprising administering to the patient an anti-IL-6 receptor (IL-6R) antibody subcutaneously, The −6R antibody relates to methods administered as a fixed dose of 162 mg per dose (eg, administered weekly or every two weeks). Disease aspects include rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis and Castleman's disease. Preferably, the anti-IL-6R antibody is tocilizumab.

  The present invention also relates to a method of treating rheumatoid arthritis in a patient comprising subcutaneously administering tocilizumab to the patient, wherein tocilizumab is administered as a fixed dose of 162 mg per dose weekly or every two weeks .

  In another embodiment, the present invention provides an article of manufacture comprising a subcutaneous administration device that delivers a fixed dose of anti-IL-6 receptor (IL-6R) antibody to a patient, the fixed dose is 162 mg, Selected from the group consisting of 324 mg and 648 mg of anti-IL-6R antibody.

  In another aspect, the present invention provides a method for inhibiting the progression of structural destruction of a joint of a patient with rheumatoid arthritis, wherein a fixed dose of anti-IL-6 receptor (IL-6R) antibody 162 mg is administered every 2 weeks. The invention relates to a method of determining at 24th or 48th week that the structural destruction of the joint has been suppressed, including subcutaneous administration to a patient.

  In addition, the present invention provides a pharmaceutical composition comprising an anti-IL-6R antibody in an amount of about 100 mg / mL to about 300 mg / mL and a hyaluronidase enzyme in an amount of about 1,400 to about 1,600 U / mL. provide.

  In another aspect, a method for treating an IL-6 mediated disease in a patient is provided, the method comprising subcutaneously administering such a pharmaceutical composition to the patient, wherein the anti-IL-6R antibody is administered per dose. It is administered at a fixed dose of 324 mg or 648 mg, for example a fixed dose is administered every 4 weeks or once a month.

  The present invention also provides a method of treating a patient's IL-6 mediated disease comprising subcutaneously administering an anti-IL-6R antibody and a hyaluronidase enzyme to the patient, wherein the anti-IL-6R antibody is 324 mg per dose or It relates to a method administered as a fixed dose of 648 mg (eg every 4 weeks or once a month).

  The invention also relates to subcutaneous administration of an anti-IL-6R antibody (eg, tocilizumab) to a patient with IL-6 mediated disease. Such diseases include autoimmune diseases, osteoporosis, neoplasms, aging, rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), systemic JIA (sJIA), articulated JIA (pcJIA), psoriatic Arthritis, Castleman's disease, Crohn's disease, multiple myeloma, rheumatic polymyalgia, glomerulonephritis, plasma cell type or plasmacytosis, myeloma (including multiple myeloma), hyperglobulinemia, Anemia, nephritis (such as mesangial proliferative nephritis), cachexia (including cancer cachexia), tumor, T cell mediated disease (eg uveitis, chronic thyroiditis, delayed type hypersensitivity, contact dermatitis) Or atopic dermatitis), lupus (including lupus nephritis and systemic lupus erythematosus), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), pancreatitis, psoriasis, osteoarthritis, adult stilosis, Mesotheliosis, Ductitis, islet transplantation (eg islet transplantation), myocardial infarction (heart failure, ischemia-induced severe arrhythmia), heart transplantation, prostate cancer, choroidal neovascularization (eg age-related macular neoplasia, idiopathic choroidal neovascularization, myopia Choroidal neovascularization, idiopathic choroidal neovascularization), muscle atrophy, chronic rejection, ocular inflammatory disease (eg panuveitis, anterior uveitis, intermediate uveitis, scleritis, keratitis, Ocular inflammation, optic neuritis, dry eye, diabetic retinopathy, proliferative vitreoretinopathy, postoperative inflammation), graft-versus-host disease (GVHD), fibrotic diseases (such as systemic sclerosis), giant Cellular arteritis (GCA), Takayasu arteritis (TA), nodular arteritis, ankylosing spondylitis and the like are included.

  The disease can be rheumatoid arthritis, juvenile idiopathic arthritis (JIA), systemic JIA (sJIA), articulated JIA (pcJIA), giant cell arteritis (GCA) or systemic sclerosis.

  In one embodiment, the anti-IL-6R antibody is administered subcutaneously to an IL-6 mediated patient as a fixed dose of 162 mg per dose, and the fixed dose is administered subcutaneously every two weeks or every 10 days.

  In another aspect, the invention provides a method of treating juvenile idiopathic arthritis (JIA) in a patient, wherein the anti-IL-6 receptor (IL-6R) antibody is an effective amount to treat the JIA. A method comprising administering to the patient subcutaneously.

  In addition, a method of treating a fibrotic disease (eg, systemic sclerosis) in a patient, wherein the anti-IL-6 receptor (IL-6R) antibody is present in an amount effective to treat the fibrotic disease. A method is provided that includes subcutaneously administering to a patient.

  Furthermore, the present invention is a method of treating giant cell arteritis (GCA) in a patient, wherein the anti-IL-6 receptor (IL-6R) antibody is in an amount effective to treat the GCA. To a method comprising subcutaneous administration.

1 represents mean sIL-6R concentration-time profiles after TCZ162 mg SC QW / Q2W administration in Japanese (MRA227) and white (NP22623) RA patients compared to TCZ4 & 8 mg IV Q4W (WA17823). Key: Japanese RA patient MRA227 study: 162 mg QW group N = 12, 162 mg Q2W group N = 12, 81 mg QW / Q2W group N = 6 to 8 and had a single dose part for 3 weeks. The 81 mg group switched regimen from Q2W to QW at week 9; white RA patients in the NP22623 study: 162 mg Q2W group N = 13, QW group N = 14. WA17823 study: 4 mg / kg IV Q4W N = 146, combined with MTX 8 mg / kg IV N = 532. Error bars indicate standard deviation. Shown are mean CRP-time profiles after administration of TCZ162 mg QW / Q2W SC in Japanese (MRA227) and Caucasian (NP22623) RA patients compared to 4 & 8 mg / kg IV Q4W (WA17822) profiles. Key: Japanese RA patients in the MRA 227 study: 162 mg QW group N = 12, 162 mg Q2W group N = 12, 81 mg Q2W / QW group includes a single dose part of 3 weeks up to 11 weeks N = 8, then N = 7. The 81 mg group switched the regimen from Q2W to QW at week 9; white RA patients in the NP22623 study: 162 mg Q2W group N = 13, QW group N = 14. WA17822 study: 4 mg / kg IV Q4W N = 152 to 211, 8 mg / kg IV combined with MTX N = 167 to 206. ULN-normal range upper limit. 2 shows the change in DAS28-ESR from baseline after TCZ administration in SC (MRA227 and NP22623) and IV (WA17822) studies. Key: SC study of Japanese RA patients (MRA 227): N = 12 for 162 mg QW group, N = 12 for 162 mg Q2W group, N = 8 for 81 mg Q2W / QW group up to 11 weeks including 3 weeks single dose part , Then N = 7. The 81 mg group switched the regimen from Q2W to QW at week 9; SC study of white RA patients (NP22623): 162 mg Q2W + MTX QW group N = 11, 162 mg QW + MTX QW group N = 12. . Comparator test WA 17822: N = 152 to 211 for 4 mg / kg Q4W + MTX QW group, N = 167 to 206 for 8 mg / kg Q4W + MTX QW group. Shown are mean TCZ concentrations ± standard deviation in serum after administration of 162 mg SC QW and Q2W in MRA227 study and 4 & 8 mg / kg IV Q4W in LRO301 study. Key: Group 1 (N = 8 until 11 weeks, then N = 7): Patients received a single dose of 81 mg SC in the 1st week, started taking Q2W in the 3rd week, and in the 9th week Switched to Q2W; second group (162 mg Q2W, N = 12): patients received a single dose of 162 mg SC in the first week and started taking Q2W in the third week; group 3 (162 mg QW, N = 12): Patients received 162 mg QW for 15 weeks until data interruption. Caucasian RA patient SC study (NP22623): 162 mg Q2W group + methotrexate (MTX) N = 13 for QW, N = 14 for 162 mg QW + MTX QW group. The PK profiles of 4 and 8 mg / kg IV infusions every 4 weeks for RA patients in the phase 2 dose setting LRO301 trial are shown for comparison. LRO301 was selected for comparison because phase 2 and phase 3 PKs were similar and phase 3 PK sampling was infrequent (the observed average PK profile could not be constructed properly) ) 2 shows the WA22762 test design described in Example 2. Figure 3 shows the NA25220B test design described in Example 3. The amino acid sequences of tocilizumab light chain (FIG. 7A; SEQ ID NO: 1) and heavy chain (FIG. 7B; SEQ ID NO: 2) are shown. 6 shows the mean (± SD) tocilizumab concentration-time profile from the cohort of the test of Example 5. FIG. 8A is a linear scale; FIG. 8B is a log-linear scale. TCZ = tocilizumab; TCZ / PH20 = co-formulation of tocilizumab and rHuPH20. The dose proportionality of tocilizumab / rHuPH20 AUC _0-inf (FIG. 9A) and C _max (FIG. 9B) is shown. Shown are mean (± SD) CRP concentration-time plots from a cohort. TCZ = tocilizumab; TCZ / PH20 = co-formulation of tocilizumab and rHuPH20. Shown are mean (± SD) IL-6 concentration-time plots from a cohort. TCZ = tocilizumab; TCZ / PH20 = co-formulation of tocilizumab and rHuPH20. Shown are mean (± SD) sIL-6R concentration-time plots from a cohort. TCZ = tocilizumab; TCZ / PH20 = co-formulation of tocilizumab and rHuPH20. Shows a comparison of IV PK profiles after 4 and 8 mg / kg every 4 weeks with SC PK profiles after 324 mg TCZ / rHuPH20 and 648 mg TCZ / rHuPH20 administration (IV data at 4 and 8 mg / kg are data from LR0320 study) Is). TCZ = tocilizumab; TCZ / PH20 = co-formulation of tocilizumab and rHuPH20. Figure 2 shows PK profile (simulated WA18221) after intravenous (IV) administration. Figure 2 shows PK profile (simulating WA18221 patient) after subcutaneous (SC) administration. Prediction model of Cmin for WA18221 test (12 mg / kg for body weight (BW) <30 kg, 8 mg / kg for BW ≧ 30 kg). Simulation model of TCZ Cmin for sJIA patients (162 mg Q2W for BW <30 kg, 162 mg QW for BW ≧ 30 kg). Simulation model of TCZ Cmin of sJIA patients (162 mg QW for BW <30 kg, 162 mg QW for BW> 30 kg). Simulation model of TCZ Cmin for sJIA patients (162 mg Q10D for BW <30 kg, 162 QW for BW ≧ 30 kg). The PCJIA50 score achievement probability (FIG. 19A) and pcJIA70 score achievement probability (FIG. 19B) for the different body weight categories of the MRA318JP test (TCZ 8 mg / kg) are shown. The numerical value on the dotted line indicates the achievement probability of the pcJIA50 score or pcJIA70 score. The area under the curve (AUC) versus body weight (BW) simulating a Japanese pediatric pcJIA patient (MRA318JP) after 6 months is shown. TCZ 8 mg / kg every 4 weeks in both body weight categories (n = 19) (FIG. 20A); 10 mg / kg or 8 mg / kg every 4 weeks in children with body weight <30 kg and ≧ 30 kg (n = 19) (FIG. 20B) . A solid line indicates a smoothing spline of all data. The dotted line (FIG. 20B) is a smoothing spline showing the baseline trend of the data with no change in the mg / kg dose for children under 30 kg. The PK profile (simulated WA19977) after IV administration every 4 weeks is shown. PK profile of 162 mg SC administration every 2 weeks (WA19977 patient simulation, FIG. 21B) is shown. 1 is a schematic view of an anti-IL-6R antibody (TCZ) administered subcutaneously to giant cell arteritis (GCA). FIG. Shown are concentration-time profiles of TCZ (FIG. 23A), sIL-6R / TCZ complex (FIG. 23B), CRP (FIG. 23C) and ESR (FIG. 23D) of the two body weight groups up to week 16 of the WA18221 study. The concentration-time profiles of TCZ (FIG. 24A), sIL-6R (FIG. 24B), CRP (FIG. 24C) and ESR (FIG. 24D) of pcJIA patients in the MRA318JP study are shown.

I. Definitions Some of the abbreviations used here: Adverse Event (AE), Auto Syringe (AI), Area Under the Curve (AUC), Weight (BW), Corticosteroid (CS), C-Reactive Protein (CRP), Every 10 days (Q10D), every week (QW), every 2 weeks (Q2W), every 4 weeks (Q4W), giant cell arteritis (GCA), interleukin 6 (IL-6), interleukin 6 receptor ( IL-6R), intravenous (IV), juvenile idiopathic arthritis (JIA), methotrexate (MTX), non-steroidal anti-inflammatory drug (NSAID), pharmacodynamics (PD), pharmacokinetics (PK), polyarticular type Juvenile idiopathic arthritis (pcJIA), prefilled syringe (PFS), rheumatoid arthritis (RA), rheumatoid factor (RF), serious adverse event (SAE), soluble interleukin-6 receptor (sIL- 6R), subcutaneous (SC), systemic juvenile idiopathic arthritis (sJIA), tocilizumab (TCZ) and water for injection (WFI).

  In the present specification, “human interleukin 6” (abbreviated as “IL-6”) is used as B cell stimulating factor 2 (BSF-2) or interferon beta 2 (IFNB2), hybridoma growth factor and CTL differentiation factor. Is also known cytokine. IL-6 was discovered as a differentiation factor contributing to B cell activation (Hirano et al., Nature 324: 73-76 (1986)) and is a multifunctional cytokine that later affects the function of various cell types. (Akira et al., Adv. In Immunology 54: 1-78 (1993)). Natural human IL-6 variants are known and are included in this definition. The amino acid sequence information of human IL-6 is disclosed, see for example www.uniprot.org/uniprot/P05231.

  For purposes herein, “human interleukin 6 receptor” (abbreviated “IL-6R”) refers to a receptor that binds to IL-6, and is associated with membrane-bound IL-6R (mIL-6R) and Contains both soluble IL-6R (sIL-6R). IL-6R can bind to the interleukin 6 signaling glycoprotein 130 to form an active receptor complex. Alternatively, post-spliced transcript variants encoding a distinct isoform of IL-6 have been reported and are included in this definition. The amino acid sequence structure of human IL-6R and its extracellular domain are described, for example, in Yamasaki et al., Science, 241: 825 (1988).

  A “neutralizing” anti-IL-6R antibody herein binds to IL-6R and may inhibit measurablely the ability of IL-6 to bind to and / or activate IL-6R. it can. Tocilizumab is an example of a neutralizing anti-IL-6R antibody.

  “Tocilizumab” or “TCZ” is a recombinant humanized monoclonal antibody that binds to the human interleukin 6 receptor (IL-6R). This is an IgG1 kappa (gamma 1, kappa) antibody having two heavy and light chains that form two antigen binding sites. In a preferred embodiment, the amino acid sequences of tocilizumab light and heavy chains comprise SEQ ID NOs: 1 and 2, respectively (see FIGS. 7A-B).

  A “native sequence” protein refers herein to a protein having the amino acid sequence of a protein found in nature, and includes naturally occurring variants of that protein. As used herein, the term encompasses proteins isolated from their natural sources or produced recombinantly.

  The term “antibody” is used herein in the broadest sense, particularly monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies) formed from at least two intact antibodies, and the desired biological activity. Antibody fragments are included as long as

As used herein, “antibody fragment” includes a portion of an intact antibody that retains antigen-binding ability. Examples of antibody fragments include Fab, Fab ′, F (ab ′) ₂ and Fv fragments; bispecific antibodies; linear antibodies; single chain antibody molecules; and multispecific antibodies formed from antibody fragments. .

  The term `` monoclonal antibody '' as used herein refers to an antibody obtained from a substantially homogeneous antibody population, i.e., except for variants that are usually present in small amounts that may occur during the production of monoclonal antibodies, Each antibody that makes up the population is identical and / or binds to the same epitope. Unlike polyclonal antibody preparations that typically include various antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to its specificity, monoclonal antibodies have the advantage that they are not contaminated by other immunoglobulins. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring that the antibody be produced in any specific manner. For example, monoclonal antibodies used in accordance with the present invention may be made by the hybridoma method first described in Kohler et al., Nature, 256: 495 (1975), or may be made by recombinant DNA methods (eg, (See U.S. Pat. No. 4,816,567). A “monoclonal antibody” can also be a phage antibody using the techniques described in, for example, Clackson et al., Nature, 352: 624-628 (1991) and Marks et al., J. Mol. Biol., 222: 581-597 (1991). It may be isolated from a library. Specific examples of monoclonal antibodies herein include chimeric antibodies, humanized antibodies and human antibodies, and antigen binding fragments thereof.

  As used herein, a monoclonal antibody is a portion of its heavy and / or light chain that is identical or homologous to the corresponding sequence of an antibody from a particular species or belonging to a particular antibody class or subclass. The remaining part of is a “chimeric” antibody (immunoglobulin) that is identical or homologous to the corresponding sequence of an antibody from another species or belonging to another antibody class or subclass, as long as it exhibits the desired biological activity. Such antibody fragments are specifically included (US Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)). Chimeric antibodies of interest herein include “primatized” antibodies comprising variable domain antigen binding sequences from non-human primates (eg, Old World monkeys such as baboons, rhesus monkeys or cynomolgus monkeys) and human constant region sequences ( US Pat. No. 5,693,780).

  “Humanized” forms of non-human (eg, murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. The majority of humanized antibodies are human immunoglobulins (recipient antibodies), and mice, rats, rabbits or non-human primates in which the recipient's hypervariable region residues have the desired specificity, affinity and ability. Substituted with the residue of a non-human species (donor antibody) such as In some cases, framework region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are found neither in the recipient antibody nor in the donor antibody. These modifications are made to further refine antibody performance. In general, a humanized antibody comprises substantially all of at least one, typically two variable domains, wherein all or substantially all hypervariable regions correspond to those of a non-human immunoglobulin, All or substantially all of the FRs except for the FR substitutions are of human immunoglobulin sequence. A humanized antibody may also comprise at least a portion of an immunoglobulin, typically a human immunoglobulin constant region. For further details, see Jones et al., Nature 321: 522-525 (1986); Riechmann et al., Nature 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992). Please refer. Humanized antibodies herein specifically include “reshaped” IL-6R antibodies described in US Pat. No. 5,795,965, which is expressly incorporated herein by reference.

  As used herein, “human antibody” includes an amino acid sequence structure corresponding to the amino acid sequence structure of an antibody that can be obtained from human B cells, and includes an antigen-binding fragment of a human antibody. Such antibodies can be identified or generated by a variety of techniques including, but not limited to, the following techniques: Gene transfer capable of producing human antibodies after immunization in the absence of endogenous immunoglobulin production Production by animals (eg mice) (eg Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90: 2551 (1993); Jakobovits et al., Nature, 362: 255-258 (1993); Bruggermann et al., Year in Immuno. 7:33 (1993) and US Pat. Nos. 5,591,669, 5,589,369, and 5,545,807); selection from phage display libraries expressing human antibodies or human antibody fragments (see, eg, McCafferty et al., Nature 348: 552-553 (1990); Johnson et al., Current Opinion in Structural Biology 3: 564-571 (1993); Clackson et al., Nature, 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1991); Griffith et al., EMBO J. 12: 725-734 (1993); see US Pat. Nos. 5,565,332 and 5,573,905); in vitro From active human B cells (see, eg, US Pat. Nos. 5,567,610 and 5,229,275); and isolation from human antibody-producing hybridomas.

As used herein, a “multispecific antibody” is an antibody that has binding specificities for at least two different epitopes. Exemplary multispecific antibodies can bind to two different epitopes of IL-6R. Alternatively, the anti-IL-6R binding arm can be a T cell receptor molecule (eg CD2 or CD3) or FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16), etc., to focus the cellular defense mechanism on the receptor. It can bind to an arm that binds to a leukocyte trigger molecule such as an Fc receptor for IgG (FcγR). Multispecific antibodies can be prepared as full length antibodies or as antibody fragments (eg F (ab ′) ₂ bispecific antibodies). Engineered antibodies with 3 or more (preferably 4) functional antigen binding sites are also contemplated (see, eg, US Patent Publication No. 2002/0004587 A1, Miller et al.).

  As used herein, an antibody includes “amino acid sequence variants” that have altered antigen binding or biological activity. Examples of such amino acid changes include improved affinity for antigen (eg, “affinity matured” antibodies), antibodies with altered Fc regions, if present, eg altered (increased or decreased) antibody dependence Antibodies having sexual cytotoxicity (ADCC) and / or complement dependent cytotoxicity (CDC) (eg, WO 00/42072, Presta, L. and WO 99/51642, Iduosogie et al. And / or antibodies with increased or decreased serum half-life (see, eg, WO 00/42072, Presta, L.).

  An “affinity mature variant” has one or more substituted residues in the hypervariable region of a parent antibody (eg, a parent chimeric, humanized or human antibody). In general, the resulting variants, selected for further development, have improved antigen binding affinity compared to the parent antibody that produced them. A convenient way to produce such substitutional variants is “affinity maturation” using phage display. Briefly, multiple hypervariable region sites (eg, 6-7 sites) are mutated to generate all possible amino substitutions at each site. The antibody variants thus produced are presented from each filamentous phage particle in a monovalent manner as a fusion with the M13 product geneIII encapsulated in the particle. The phage display variant is then screened for its biological activity (eg, binding affinity). To identify hypervariable region site candidates for modification, alanine scanning mutagenesis can be performed to identify hypervariable region residues that contribute substantially to antigen binding. Alternatively, or in addition, it may be useful to analyze the crystal structure of the antigen-antibody complex to identify contact points between the antibody and human IL-2R. Such contact residues and neighboring residues are candidates for substitution according to the techniques detailed herein. Once such variants are produced, the panel of variants can be screened and antibodies with improved affinity can be selected for further development.

  The antibodies herein can be conjugated with “heterologous molecules”, eg, to increase half-life, stability, or otherwise improve the antibody. For example, the antibody can be linked to one of a variety of non-proteinaceous polymers such as, for example, polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylene, or a copolymer of polyethylene glycol and polypropylene glycol. Antibody fragments such as Fab 'linked to one or more PEG molecules are an exemplary embodiment of the invention.

  The antibodies herein may be “glycosylated variants” so that any carbohydrate attached to the Fc region is altered if present. For example, an antibody in which a mature carbohydrate structure lacking fucose is attached to an antibody Fc region is described in US Patent Publication No. 2003/0157108 (Presta, L.). See also US Patent Publication No. 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd.). Antibodies having bisecting N-acetylglucosamine (GlcNAc) as a carbohydrate attached to the antibody Fc region are referenced in WO2003 / 011878, Jean-Mairet et al. And US Pat. No. 6,602,684, Umana et al. An antibody having at least one galactose residue in an oligosaccharide attached to an antibody Fc region has been reported in International Publication No. 1997/30087, Patel et al. See also WO 1998/58964 (Raju, S.) and WO 1999/22764 (Raju, S.) for antibodies with modified carbohydrates attached to their Fc region. See also US Patent Publication No. 2005/0123546 (Umana et al.) Which describes antibodies having modified glycosylation.

The term “hypervariable region” when used herein refers to the amino acid residues of an antibody which are responsible for antigen binding. The hypervariable region is a “complementarity determining region” or “CDR” (eg, residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) of the light chain variable domain and the heavy chain variable domain. Residues 31-35 (H1), 50-65 (H2) and 95-102 (H3); Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition National Institutes of Health, Public Health Department, Bethesda, MD (1991)) and / or residues of the “hypervariable loop” (eg residues 26-32 (L1), 50-52 (L2) and 91-96 (L3) of the light chain variable domain) and of the heavy chain variable domain Residues 26-32 (H1), 53-55 (H2) and 96-101 (H3); Chothia and Lesk J. Mol. Biol. 196: 901-917 (1987)). “Framework” or “FR” residues are other variable domain residues of the hypervariable region residues as herein defined. The hypervariable regions of tocilizumab include the following:
L1-Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn (SEQ ID NO: 3);
L2-Tyr Thr Ser Arg Leu His Ser (SEQ ID NO: 4);
L3-Gln Gln Gly Asn Thr Leu Pro Tyr Thr (SEQ ID NO: 5);
H1-Ser Asp His Ala Trp Ser (SEQ ID NO: 6);
H2-Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser (SEQ ID NO: 7); and H3-Ser Leu Ala Arg Thr Thr Ala Met AspT number

  In one embodiment herein, the IL-6R antibody comprises the hypervariable region of tocilizumab.

  A “full length antibody” is an antibody comprising an antigen binding variable region and a light chain constant domain (CL) and heavy chain constant domains CH1, CH2 and CH3. The constant domain may be a native sequence constant domain (eg, a human native sequence constant domain) or an amino acid sequence variant thereof. Preferably, the full length antibody has one or more effector functions. Tocilizumab is an example of a full-length antibody.

  A “naked antibody” is an antibody (as defined herein) that is not conjugated to a heterologous molecule such as a cytotoxic moiety, polymer or radiolabel.

  Antibody “effector functions” refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody dependent cytotoxicity (ADCC) and the like.

  Depending on the amino acid sequence of the heavy chain constant domain, full-length antibodies are assigned to different “classes”. The five major classes of full-length antibodies are IgA, IgD, IgE, IgG and IgM, some of which are further divided into "subclasses" (isotypes) such as IgGl, IgG2, IgG3, IgG4, IgA and IgA2. Can do. The heavy-chain constant domains that correspond to the different classes of antibodies are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional structures of different classes of immunoglobulins are well known.

  As used herein, the term “recombinant antibody” refers to an antibody (eg, a chimeric, humanized or human antibody or antigen-binding fragment thereof) expressed by a recombinant host cell comprising a nucleic acid encoding the antibody. . Examples of “host cells” that produce recombinant antibodies include: (1) Chinese hamster ovary (CHO), COS, myeloma cells (including Y0 and NS0 cells), baby hamster kidney (BHK), Hela and Vero cells, etc. (2) insect cells such as sf9, sf21 and Tn5; (3) plant cells belonging to the genus tobacco (eg tobacco); (4) eg belonging to the genus Saccharomyces (eg budding yeast) or Aspergillus Yeast cells belonging to (for example, Aspergillus niger); (5) bacterial cells such as E. coli cells or Bacillus subtilis cells.

As used herein, “specific binding” or “specifically binds” refers to an antibody that selectively or preferentially binds to an IL-6R antigen. Preferably, the affinity for the antigen has a Kd value of 10 ⁻⁹ mol / l or lower (eg 10 ⁻¹⁰ mol / l), preferably a Kd value of 10 ⁻¹⁰ mol / l or lower (eg 10 ⁻¹² mol / l). mol / l). Binding affinity is determined by standard binding assays such as surface plasmon resonance (BIACORE®).

  For the purposes of this specification, the term “IL-6 mediated disease” means that activation of IL-6R to IL-6 causes the disease and / or anti-IL-6R antibody therapy It refers to a disease or illness that can be used as a treatment method for the disease or illness. Examples of such diseases include autoimmune diseases, osteoporosis, neoplasms, aging, rheumatoid arthritis (RA), juvenile idiopathic arthritis (including systemic JIA and polyarticular JIA), psoriatic arthritis , Castleman's disease, Crohn's disease, multiple myeloma, rheumatic polymyalgia, glomerulonephritis, plasma cell type or plasmacytosis, myeloma (including multiple myeloma), hyperglobulinemia, anemia , Nephritis (such as mesangial proliferative nephritis), cachexia (including cancer cachexia), tumors, T cell mediated diseases (eg uveitis, chronic thyroiditis, delayed type hypersensitivity, contact dermatitis or Atopic dermatitis), lupus (including lupus nephritis and systemic lupus erythematosus), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), pancreatitis, psoriasis, osteoarthritis, adult stilosis, moderate Dermatosis, vasculitis, island Transplantation (eg islet transplantation), myocardial infarction (heart failure, ischemia-induced severe arrhythmia), heart transplantation, prostate cancer, choroidal neovascularization (eg age-related macular neoplasia, idiopathic choroidal neovascularization, myopic choroidal neovascularization) , Idiopathic choroidal neovascularization), muscular atrophy, chronic rejection, ocular inflammatory disease (eg panuveitis, anterior uveitis, intermediate uveitis, scleritis, keratitis, ocular inflammation, Optic neuritis, dry eye, diabetic retinopathy, proliferative vitreoretinopathy, postoperative inflammation), graft-versus-host disease (GVHD), fibrotic diseases (such as systemic sclerosis), giant cell arteritis (GCA), Takayasu arteritis (TA), nodular arteritis, ankylosing spondylitis and the like.

  In one embodiment, the IL-6 mediated disease is rheumatoid arthritis.

  In one embodiment, the IL-6 mediated disease is juvenile idiopathic arthritis (JIA).

  In one embodiment, the IL-6 mediated disease is systemic JIA (sJIA).

  In one embodiment, the IL-6 mediated disease is articulated JIA (pcJIA).

  In one embodiment, the IL-6 mediated disease is systemic sclerosis.

  In one embodiment, the IL-6 mediated disease is giant cell arteritis (GCA).

  In one embodiment, the IL-6 mediated disease is psoriatic arthritis.

  In one embodiment, the IL-6 mediated disease is uveitis.

  As used herein, “rheumatoid arthritis” (abbreviated as “RA”) is a chronic systemic inflammatory disease that can affect many tissues and organs but primarily attacks synovial joints. Point to. RA must be diagnosed according to the Rheumatoid Arthritis Classification Criteria of the American College of Rheumatology (ACR), revised in 1987 or 2000, or according to any similar criteria. Physiological indicators of RA include bilaterally symmetric joint expansion, although not invariant to rheumatoid arthritis. Spindle-type dilation of the proximal interphalangeal (PIP) joint of the hand as well as metacarpal (MCP), wrist, elbow, knee, heel and metatarsophalangeal (MTP) joints, and swelling Easily recognized. The most sensitive test for joint inflammation is passive pain, and inflammation and structural deformation often limit the range of motion of the affected joint. Typical visible changes include MCP joints with deformed fingers toward the ulna, MCP and PIP joints overextension or hyperflexion, elbow flexion contractures and carpal and toe subluxation.

  By “active rheumatoid arthritis” patient is meant a patient with symptoms of rheumatoid arthritis that is active and not latent. In one embodiment, such patients have a moderate to severe active RA disease duration of ≧ 6 months at the baseline visit. In one embodiment, such patients have (1) number of joints expanded (SJC) ≧ 4 (number of 66 joints), (2) number of tender joints (TJC) ≧ 4 (number of 68 joints) and / or C-reactive protein (CRP) ≧ having upper limit of normal at screening visit (ULN).

  Examples of “disease modifying anti-rheumatic drugs” or “DMARD” include hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, azathioprine, D-penicillamine, gold salt (oral), gold salt (intramuscular), minocycline, cyclosporin A and Examples include cyclosporine, including topical cyclosporine, staphylococcal protein A and TNF inhibitors (see below) and their salts, variants and derivatives. Exemplary DMARDs herein are non-biological DMARDs, including in particular azathioprine, chloroquine, hydroxychloroquine, leflunomide, methotrexate and suflasalazine, where methotrexate is a DMARD according to one embodiment of the present invention.

  For purposes of this specification, “tumor necrosis factor” (abbreviated as “TNF”) is an amino acid described in Pennica et al., Nature, 312: 721 (1984) or Aggarwal et al., JBC, 260: 2345 (1985). Refers to a human TNF-alpha molecule containing the sequence.

  As used herein, a “TNF inhibitor” is an agent that inhibits the biological function of TNF-alpha to some extent by generally binding to TNF-alpha and neutralizing its activity. Examples of TNF inhibitors specifically contemplated herein include etanercept (ENBREL®), infliximab (Remicade®) and adalimumab (HUMIRA®), certolizumab pegol (CIMZIA ( Registered trademark)) and golimumab (SIMPONI (registered trademark)).

  A “insufficient DMARD responder” subject is an inadequate response to past or current treatment with one or more DMARDs (including one or more TNF inhibitors) due to toxicity or poor efficacy An individual who has experienced.

  A subject with an “insufficient TNF inhibitor responder” experiences an inadequate response to past or current treatment with one or more TNF inhibitors due to toxicity or poor efficacy. In one embodiment, such a patient has received, for example, etanercept ≧ 3 months, 25 mg twice a week, or at least 4 infusions of infliximab at ≧ 3 mg / kg. There was an inadequate response.

  An “insufficient methotrexate responder” is a patient experiencing an inadequate response to past or current treatment with methotrexate due to toxicity or ineffectiveness. In one embodiment, the patient has been on methotrexate (10-25 mg / week) treatment for at least 12 weeks but still has active disease.

“Fixed dose” herein refers to a dose of a drug, such as an anti-IL-6R antibody, that is administered regardless of the patient's body weight or body surface area (BSA), ie not administered in mg / kg or mg / m ² doses. Point to.

  “Treatment” of a subject as used herein refers to both therapeutic treatment and prophylactic or preventative measures.

  The expression “effective amount” refers to the amount of antibody that is effective in the treatment of IL-6 disease. When the disease is RA, such an effective amount is a reduction in any one or more signs or symptoms of RA (eg, achieving an ACR20, ACR50 or ACR70 response at weeks 24 and / or 48), disease activity May result in reduced sex (eg, disease activity score, DAS20), ACR hybrid, delayed progression of structural joint destruction, improved physical function, and the like. In one embodiment, such a clinical response is comparable to that obtained with an intravenously administered anti-IL-6R antibody.

  The expression “suppressing the progression of structural joint destruction” in RA patients refers to preventing or delaying structural joint destruction due to RA, for example based on the number of eroded joints and / or the joint destruction score. Methods for measuring the progression of structural joint destruction are known to those skilled in the art and include, but are not limited to, the Genant modified total sharp score (TSS), the erosion score (ES) and / or the joint space narrowing (JSN) score.

  The term “immunosuppressive agent” as used herein for adjuvant treatment refers to a substance that acts to suppress or mask the immune system of the mammal being treated here. This may include substances that suppress cytokine production, down-regulate or suppress self-antigen expression, or mask MHC antigens. Examples of such agents include 2-amino-6-aryl-5-substituted pyrimidines (see US Pat. No. 4,665,077); nonsteroidal anti-inflammatory drugs (NSAIDs); glucos such as ganciclovir, tacrolimus, cortisol or aldosterone. Anti-inflammatory agents such as corticoids, cyclooxygenase inhibitors, 5-lipoxygenase inhibitors or leukotriene receptor antagonists; purine receptor antagonists such as azathioprine or mycophenolate mofetil (MMF); alkylating agents such as cyclophosphamide; bromocriptine; Danazol; Dapsone; glutaraldehyde (masking MHC antigens as described in US Pat. No. 4,120,649); anti-idiotype antibodies to MHC antigens and MHC fragments; cyclosporin A; corticosteroids or groups Steroids such as cococorticosteroids or analogs of glucocorticoids, eg prednisone, SOLU-MEDROL® methylprednisolone succinate and methylprednisolone sodium and dexamethasone; dihydrofolate reductase inhibitors such as methotrexate (oral or subcutaneous); Antimalarial drugs such as quinine and hydroxychloroquinine; sulfasalazine; leflunomide; anti-interferon-alpha, -beta or -gamma antibody, anti-tumor necrosis factor (TNF) -alpha antibody (infliximab (Remicade®) or adalimumab), Anti-TNF-alpha immunoadhesin (etanercept), anti-TNF-beta antibody, anti-interleukin-2 (IL-2) antibody and anti-IL-2 receptor antibody and anti-inter Cytokine antagonists such as cytokine antibodies or cytokine receptor antibodies, including leukin-6 (IL-6) receptor antibodies and antagonists; anti-LFA-1 antibodies including anti-CD11a and anti-CD18 antibodies; anti-L3T4 antibodies; heterologous anti-lymphocytes Globulin: pan T antibody, preferably anti-CD3 or anti-CD4 / CD4a antibody; soluble peptide containing LFA-3 binding domain (WO 90/08187 published 26 July 1990); streptokinase; transforming growth factor Streptodolase; Host RNA or DNA; FK506; RS-61443; Chlorambucil; Deoxyspagarin; Rapamycin; T cell receptor (Cohen et al., US Pat. No. 5,114,721); T cell receptor Body fragments (Offner et al., Science, 251: 430-432 (1991); WO 90/11294; Ianeway, Na ture, 341: 482 (1989); and WO 91/01133); BAFF antagonists such as BAFF and BR3 and zTNF4 (reviewed by Mackay and Mackay, Trends Immunol., 23: 113-5 (2002) Blocking antibodies against CD40-CD40 ligand (eg, Durie et al., Science, 261: 1328-30 (1993); Mohan et al., J. Immunol., 154: 1470-80 (1995)) and CTLA4-Ig (Finck Et al., Science, 265: 1225-7 (1994)), biologics that inhibit T cell helper signals such as anti-CD40 receptor or anti-CD40 ligand (CD154); and T cell receptor antibodies such as T10B9 ( EP340, 109). Some immunosuppressive agents herein are also DMARDs such as methotrexate. Examples of immunosuppressive agents herein include cyclophosphamide, chlorambucil, azathioprine, leflunomide, MMF or methotrexate.

  The “CD20” antigen or “CD20” is an approximately 35 kDa, non-glycosylated phosphate protein found on the surface of more than 90% of peripheral blood or lymphoid B cells. CD20 is displayed on both normal and malignant B cells, but not on stem cells. Alternative names for CD20 in the literature include “B lymphocyte restricted antigen” and “Bp35”. The CD20 antigen is described, for example, in Clark et al., Proc. Natl. Acad. Sci. (USA) 82: 1766 (1985).

Examples of CD20 antibodies include the following: “C2B8” (“Rituxan® / Mabsera®”) currently called “Rituximab” (US Pat. No. 5,736,137); commercially available from Biogen Idec Yttrium- [90] -labeled 2B8 mouse antibody referred to as “Y2B8” or “Ibritumomab tiuxetane” (Zevalin®) (eg, US Pat. No. 5,736,137; accession number HB11388 on June 22, 1993) 2B8) deposited at ATCC; mouse IgG2a “B1”, also known as “tositumomab”, optionally labeled with ¹³¹ I and commercially available from Corixa as “131I-B1” or “iodine I131 tositumomab” antibody (BEXAR ^™ ) (eg, US See also patent 5,595,721); mouse monoclonal antibody “1F5” (eg Press et al. Blood 69 (2): 584-591 (1987) and “Fre Muvar patched "or variants thereof containing humanized 1F5 (eg, WO2003 / 002607, Leung, S .; ATCC deposit HB-96450); mouse 2H7 and chimeric 2H7 antibodies (eg, US Pat. No. 5,677,180); Humanized 2H7 (eg as described in WO 2004/056312 (Lowman et al.) And below); HUMAX-CD20 ^™ fully human, high affinity antibody (Genmab, Denmark) targeting the CD20 molecule in the cell membrane of B cells See, for example, Glennie and van de Winkel, Drug Discovery Today 8: 503-510 (2003) and Cragg et al., Blood 101: 1045-1052 (2003))); WO 2004/035607 and WO 2005 / Human monoclonal antibody described in US Pat. No. 103081 (Teeling et al., GenMab / Medarex); antibody having an N-glycoside-linked glycan Fc region described in US Patent Publication No. 2004/0093621 (Shitara et al.); HB20-3, HB20 -4, HB20-2 And monoclonal antibodies and antigen-binding fragments that bind CD20, such as MB20-11 (eg, WO 2005/000901, Tedder et al.); Single chain proteins that bind CD20 (eg, US Patent Publication No. 2005/0186216 (Ledbetter and Hayden-Ledbetter); U.S. Patent Publication No. 2005/0202534 (Hayden-Ledbetter and Ledbetter); U.S. Patent Publication No. 2005/0202028 (Hayden-Ledbette and Ledbetter); U.S. Patent Publication No. 2005/0202023 (Hayden-Ledbetter and Ledbetter, Trubion Pharm Inc.); for example AME series antibodies such as the AME-33 ^™ antibody described in WO 2004/103404 and US Patent Publication No. 2005/0025764 (Watkins et al., Applied Molecular Evolution, Inc.). And a CD20 binding molecule such as a CD20 antibody having an Fc variant as described, for example, in WO 2005/070963 (Allan et al., Applied Molecular Evolution, Inc.); WO 2005/016969 and US Patent Publication No. 200 CD20 binding molecules such as those described in 5/0069545 (Carr et al.); Bispecific antibodies such as those described in WO 2005/014618 (Chang et al.); Eg US Patent Publication No. 2005/0106108 (Leung and Humanized LL2 monoclonal antibody described in Hansen; Immunomedics); for example, chimeric or humanized B-Ly1 against CD20 described in WO 2005/044859 and US Patent Publication 2005/0123546 (Umana et al .; GlycArt Biotechnology AG) Antibodies; A20 antibodies such as chimeric or humanized A20 antibodies (cA20, hA20, respectively) or variants thereof and IMMUN-106 (eg, US 2003/0219433, Immunomedics); and international leukocyte typing workshops (eg, Leukocyte Typing III). (McMichael version., P. 440, Oxford University Press (1987), Valentine et al.) Monoclonal antibodies L27, G28-2, 93-1B3, B -C1 or NU-B2. Preferred CD20 antibodies herein are chimeric, humanized or human CD20 antibodies, more preferably rituximab, humanized 2H7, chimeric or humanized A20 antibody (Immunomedics), HUMAX-CD20 ^TM human CD20 antibody (Genmab) and Immunoglobulin / protein that binds to CD20 (Trubion Pharm Inc.).

  The terms “rituximab” or “Rituxan®” herein are generally referred to as genetically engineered chimeric mouse / human monoclonals, referred to as “C2B8” in US Pat. No. 7,381,560 (Anderson et al.) Against the CD20 antigen. Refers to an antibody and includes fragments thereof that retain the ability to bind to CD20.

  Examples of “non-steroidal anti-inflammatory drugs” or “NSAIDs” include aspirin, acetylsalicylic acid, ibuprofen, flurbiprofen, naproxen, indomethacin, sulindac, tolmetine, phenylbutazone, diflufenac, ketoprofen, benolylate, mefenamic acid, methotrexate , Fenbufen, azapropazone; celecoxib (COX-2 inhibitors such as CELEBREX®); 4- (5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) benzenesulfone And amide, valdecoxib (Vextra (registered trademark)), meloxicam (MOBIC (registered trademark)), GR253035 (Glaxo Wellcome); and MK966 (Merck Sharp & Dohme), and salts and derivatives thereof are also included. These are aspirin , Naproxen, ibuprofen, indomethacin or tolmetin.

  “Corticosteroid” refers to any of a plurality of synthetic or natural substances that have the general chemical structure of steroids and that mimic or augment the effects of natural corticosteroids. Examples of synthetic corticosteroids include prednisone, prednisolone (including methylprednisolone such as SOLU-MEDROL® methylprednisolone sodium succinate), dexamethasone or dexamethasone triamcinolone, hydrocortisone and betamethasone. Preferred corticosteroids herein are prednisone, methylprednisolone, hydrocortisone or dexamethasone.

  A “medicament” is an active agent that treats joint destruction or its symptoms or side effects.

  The term “pharmaceutical formulation” refers to a preparation that is in a form such that the biological activity of one or more active ingredients is effective and does not contain additional ingredients that are unacceptably toxic to the patient receiving the formulation. Point to. Such formulations are sterile.

  A “sterile” formulation is sterile, i.e. free of any microorganisms and their spores.

  A “stable” formulation essentially maintains the physical and / or chemical stability and / or biological activity of all proteins contained in the formulation, for example at an intended storage temperature of 2-8 ° C. Refers to things. Preferably, the physical and chemical stability of the formulation and its biological activity are essentially maintained upon storage. The storage period is generally selected based on the intended shelf life of the formulation. Furthermore, the formulations are preferably stable after freezing (eg up to −20 ° C.) and thawing, eg after one or more cycles of freezing and thawing. Various analytical methods for measuring protein stability are available in the art, e.g., Peptide and Protein Drug Delivery, 247-301, Vincent Lee Edition, Marcel Dekker, Inc., New York, New York, Pubs. 1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993). Stability can be measured at a selected temperature for a selected time period. Stability can be assessed qualitatively and / or quantitatively in a wide variety of ways, assessing aggregate formation (eg, measuring turbidity using size exclusion chromatography and / or visually); cation exchange chromatography Assessment of charge heterogeneity using chromatography or capillary zone electrophoresis; comparison of reduced and intact antibodies by SDS-PAGE analysis; assessment of antibody biological activity or antigen binding function, and the like.

  “Stabilizer” refers herein to an excipient or mixture of two or more excipients that stabilize a pharmaceutical formulation. For example, the stabilizer can avoid destabilization of the formulation by freeze-thawing or other heat induction. Exemplary stabilizers herein include surfactants and amino acids (and derivatives thereof) such as arginine or methionine.

The term “surfactant” as used herein refers to a pharmaceutically acceptable surfactant. In the formulations of the present invention, the amount of surfactant is described as a percentage expressed in weight / volume. The most commonly used weight / volume unit is mg / mL. Suitable examples of pharmaceutically acceptable surfactants include polyoxyethylene-sorbitan fatty acid esters, polyethylene-polypropylene glycol, polyoxyethylene-stearic acid, polyoxyethylene alkyl ethers (eg polyoxyethylene monolauryl ether, alkyl Phenyl polyoxy-ethylene ether (Triton-X), polyoxyethylene-polyoxypropylene copolymer (poloxamer, pluronic) and sodium dodecyl sulfate (SDS) The most suitable polyoxyethylene sorbitan fatty acid ester is polysorbate 20 (sold under the trademark TWEEN 20®) and polysorbate 80 (sold under the trademark TWEEN 80®). - polypropylene copolymer, Pluronic sold under the name (R) F68 or Poloxamer 188 (TM) Preferred polyoxyethylene -. Stearic acid is one sold under the trademark of MYRJ ^TM The most suitable polyoxy-ethylene alkyl esters are those sold under the trademark BRIJ ^™ The most suitable alkylphenol poly-oxyethylene ethers are sold under the trade name Triton-X®. Yes.

  The term “buffer” as used herein refers to a pharmaceutically acceptable buffer that resists changes in pH by the action of its acid / base conjugate component. The pH of the formulation may range from 5 to 7, for example 5.5 to 6.5, most preferably about pH 6, and the buffer used will achieve such a desired pH of the formulation. Suitable pharmaceutically acceptable buffers of the present invention include, but are not limited to, histidine-buffer, citrate-buffer, gluconate-buffer, succinate-buffer, acetate-buffer, glycylglycine and other organic acid buffers And phosphate-buffer. Preferred buffers include L-histidine or a mixture of L-histidine and L-histidine hydrochloride, using a potential pH adjustment using isotonic agents and acids or bases known to those skilled in the art. Most preferred is histidine (eg L-histidine).

  “Isotonic” means that the subject formulation has essentially the same osmotic pressure as human blood. Isotonic formulations generally have an osmotic pressure from about 250 to 350 mOsm. The isotonicity can be measured using, for example, a vapor pressure type or ice freezing type osmometer.

  A “liquid formulation” or “aqueous formulation” of the present invention refers to a formulation that is liquid at a temperature of at least about 2 to about 8 ° C.

  The term “lyophilized formulation” refers to a formulation that has been freeze-dried and then sublimated from frozen material using any freeze-drying method known in the art, such as, for example, a commercial freeze-drying apparatus. Such a formulation can be redissolved in an appropriate diluent such as water, sterile water for injection, physiological saline, etc., to produce a redissolved liquid formulation suitable for administration to a subject.

  “Hyaluronan” (also referred to as “HA”, “hyaluronic acid” or “hyaluronate”) is an anionic, non-sulfated glycosaminoglycan that is widely distributed in connective, epithelial and neural tissues.

“Hyaluronidase” is an enzyme that degrades hyaluronic acid. In humans, there are six related genes including HYALPI (pseudogene), HYAL1, HYAL2, HYAL3, HYAL4 and PH20 / SPAM1. As used herein, the term hyaluronidase encompasses “acid-active” enzymes (such as HYAL1) and “neutral-active” enzymes (such as PH20). It also includes an enzyme with or without a glycosylphosphatidylinositol anchor; preferably, the hyaluronidase is soluble or has no anchor. Hyaluronidase is included in pharmaceutical formulations to facilitate subcutaneous administration of therapeutic agents, reduce interstitial viscosity, allow for increased SC dosage, and / or increase absorption and dispersion of another injection Can be done. The hyaluronidase enzyme in the pharmaceutical formulation herein is characterized by having no adverse effects on the molecular binding properties of the anti-IL-6R antibody in the formulation, and is capable of delivering the anti-IL-6R antibody to the systemic circulation. Although modified, it does not have any properties that can provide or contribute to the therapeutic effects of systemically absorbed anti-IL-6R antibodies. See also WO 2004/078140, WO 2006/091871 and US Pat. No. 7,767,429 for the hyaluronidase of the present invention. Hyaluronidase products approved in the EU countries include HYAASE®. US approved animal-derived hyaluronidase products include VITRASE ^™ , HYDRASE ^™, and AMPHADASE ^™ . A preferred hyaluronidase herein is recombinant human PH20.

  “Recombinant human PH20” (abbreviated “rHuPH20”) refers to a soluble neutral pH active enzyme having a truncated human PH20 amino acid sequence. This can be synthesized using a 35 amino acid signal peptide that is removed from the N-terminus during the process of secretion to yield the N-terminal amino acid sequence found in some bovine hyaluronidase preparations. Preferably, the rHuPH20 herein has the amino acid sequence set forth in US Pat. No. 7,767,429 available at CAS Registry Number 757971-58-7, or expressly incorporated herein by reference, with a molecular weight of It is about 61 kDa. See also Frost, G.I., “Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration”, Expert Opinion on Drug Delivery 4: 427-440 (2007)). As used herein, this term includes rHuPH20 (HYLENEX®) commercially available from Halozyme Therapeutics Inc.

  “Subcutaneous administration device” refers to devices such as syringes, syringes, infusion pumps, injection pens, needle-free devices, patch delivery systems, etc., and are designed or designed to administer drugs or pharmaceutical formulations by the subcutaneous route . In one embodiment, the device administers about 0.9 mL, 1.8 mL, or 3.6 mL of pharmaceutical formulation.

  “Packaging” is used to refer to instructions that are typically enclosed in a commercial package of therapeutics, and information about indications, uses, usage, doses, contraindications, and other therapeutics used in conjunction with the product And / or warnings regarding the use of such therapeutic agents, etc. are described.

  As used herein, “fibrotic disease” refers to a disease in which excess fibrous connective tissue is formed in an organ and / or tissue. Examples of fibrotic diseases herein include systemic sclerosis (scleroderma), keloids, hypertrophic scars, burn scars, liver fibrosis, cirrhosis, pulmonary hypertension (including idiopathic pulmonary fibrosis, IPF) ) Pulmonary fibrosis, cardiac fibrosis, renal fibrosis, liver fibrosis and the like. In one embodiment, the fibrotic disorder is systemic sclerosis.

  “Systemic sclerosis” (SSc) or “scleroderma” is a complex and heterogeneous disease with major features such as skin and tissue fibrosis, vascular degeneration and autoantibodies versus various cellular antigens . The clinical symptoms of systemic sclerosis can range from limited skin lesions to severe visceral dysfunction. Visceral pathology is a major factor in the prevalence of the disease, with the most frequently involved organs being kidney, esophagus, heart and lung. There are two generally recognized subgroups of SSc classification: localized skin SSc (lcSSc) and diffuse skin SSc (dcSSc). Gabrielli et al. Mechanisms of disease. Scleroderma. N Engl J Med 360: 1989-2003 (2009).

In one embodiment, patients with systemic sclerosis are categorized based on the following systemic scleroderma classification criteria of the American College of Rheumatology (ACR).
Key indicators: Proximal extensive (trunk) sclerosis (skin hardening, thickening and non-indentation sclerosis); and secondary indicators: (1) spondylosis (hand and / or toe only), (2) fingertip concave scar or finger abdominal defect (pulp defect) and (3) bilateral lower lung field fibrosis, etc., patients with systemic sclerosis are primary indicators or three secondary indicators It is necessary to satisfy two of them. See Arthritis Rheum 23: 581-90 (1980), the systemic sclerosis (scleroderma) preliminary classification criteria of the American College of Rheumatology Association of Diagnosis and Treatment Criteria, Subcommittee on Clerosis Standards.

II. Production of anti-IL-6R antibodies The methods and articles of manufacture of the invention use or incorporate antibodies that bind to human IL-6R. The IL-6R antigen used for antibody production or screening can be, for example, soluble IL-6R or a portion thereof (eg, the extracellular domain) containing the desired epitope. Alternatively, or in addition, cells expressing IL-6R on the cell surface may be used to produce or screen for antibodies. Other forms of IL-6R useful for antibody production will be apparent to those skilled in the art.

  In one embodiment, the antibody is an antibody fragment, and various such fragments are described above.

  In another embodiment, the antibody is an intact or full-length antibody. Depending on the amino acid sequence of the heavy chain constant domain, intact antibodies can be assigned to different classes. The five major classes of intact antibodies are IgA, IgD, IgE, IgG and IgM, some of which are further divided into “subclasses” (isotypes) such as IgGl, IgG2, IgG3, IgG4, IgA and IgA2. Can do. The heavy chain constant domains that correspond to the different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional structures of different classes of immunoglobulins are well known. In a preferred embodiment, the anti-IL-6R antibody is an IgG1 or IgM antibody.

  Antibody production methods are known, examples of which are described in the definitions section herein. In preferred embodiments, the antibody is a chimeric, humanized or human antibody or antigen-binding fragment thereof. Preferably the antibody is a humanized full length antibody.

  Various techniques are available for determining the binding of antibody to IL-6R. One assay is an enzyme linked immunosorbent assay (ELISA), which evaluates the ability to bind human IL-6R. See, for example, US Pat. No. 5,795,965. By this assay, a plate coated with IL-6R (eg, recombinant sIL-6R) is incubated with a sample containing an anti-IL-6R antibody and the binding of the antibody to sIL-6R is determined.

  Preferably, the anti-IL-6R antibody neutralizes IL-6 activity, for example by inhibiting the binding of IL-6 and IL-6R. Exemplary methods for assessing such inhibition are disclosed, for example, in US Pat. Nos. 5,670,373 and 5,795,965. According to this method, the ability of antibodies to compete for IL-6R with IL-6 is evaluated. For example, a plate is coated with IL-6R (eg, recombinant sIL-6R), a sample containing labeled IL-6 and anti-IL-6R antibody is added, and the antibody labeled IL-6 and IL-6R are added. The ability to inhibit binding is measured. See U.S. Pat. No. 5,795,965. Alternatively or in addition, the binding of IL-6 to membrane bound IL-6R is identified according to the method of Taga et al. Assays to confirm neutralizing activity using the IL-6-dependent human T cell leukemia KT3 strain are also available, see US Pat. No. 5,670,373 and Shimizu et al. Blood 72: 1826 (1988).

  Non-limiting examples of anti-IL-6R antibodies herein include PM-1 antibody (Hirata et al., J. Immunol. 143: 2900-2906 (1989), AUK12-20, AUK64-7 and AUK146-15 antibodies. (US Patent No. 5,795,965) as well as humanized variants thereof, such as tocilizumab, see US Patent No. 5,795,965.Preferred examples of reshaped human antibodies used in the present invention include humanized or renatured antibodies. And anti-interleukin (IL-6) receptor antibodies formed (hPM-1 or MRA) (see US Pat. No. 5,795,965).

  The antibody of the present invention is preferably produced recombinantly in a host cell transformed with nucleic acid sequences encoding its heavy and light chains (eg, the host cell is transformed with nucleic acid in one or more vectors). Have been). Preferred host cells are mammalian cells, most preferably Chinese hamster ovary (CHO) cells.

III. Pharmaceutical Formulations A therapeutic formulation of an antibody used in accordance with the present invention is prepared by mixing an antibody of the desired purity with any pharmaceutically acceptable carrier, excipient or stabilizer, as a lyophilized formulation or an aqueous solution. Preserved (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Acceptable carriers, excipients or stabilizers are harmless to the recipient at the dosages and concentrations utilized and include the following: buffers such as phosphoric acid, citric acid and other organic acids; ascorbic acid and methionine (Octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and preservatives (such as m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; glycine, glutamine, asparagine, hist Amino acids such as glucose, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium Metal complexes (eg Zn-protein complexes); and / or nonionic surfactants such as TWEEN ^™ , Pluronic ^™ or polyethylene glycol (PEG).

  The formulations herein may also contain more than one active compound as necessary, preferably those with complementary activities that do not adversely affect each other. The type and effective amount of such medicament depends, for example, on the amount of antibody present in the formulation and the clinical parameters of the subject. Exemplary such medicaments are described below.

  The active ingredient can also be used in colloidal drug delivery systems (for example, in microcapsules prepared by coacervation or interfacial polymerization, for example hydroxymethylcellulose or gelatin-microcapsules and poly- (methyl methacrylate) microcapsules, respectively. Liposomes, albumin microparticles, microemulsions, nanoparticles and nanocapsules) or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained release modifiers can be prepared. A suitable example of a sustained release modifier is an anti-permeable matrix of a solid hydrophobic polymer containing antibodies, which matrix takes the form of a molded article such as a film or microcapsule. Examples of sustained release matrices include polyesters, hydrogels (eg poly (2-hydroxyethyl-methacrylate) or poly (vinyl alcohol)), polylactic acid (US Pat. No. 3,773,919), L-glutamic acid and γ ethyl-L-glutamic acid Degradable butyric acid-glycolic acid copolymers such as polymers, non-degradable ethylene-vinyl acetate, LUPRON DEPOT ^™ (injectable microparticles composed of butyric acid-glycolic acid copolymer and leuprolide acetate) and poly-D- (-)-3-hydroxybutyric acid is included.

  Formulations used in vivo must be sterile. This can be easily accomplished by filtration through a sterile filtration membrane.

  In one embodiment, the anti-IL-6R antibody-containing liquid formulation of the present invention has a high concentration of anti-IL-6R antibody, preferably 50 to 300 mg / mL, more preferably 100 to 300 mg / mL, even more preferably 120 to 250 mg. / ML, more preferably 150 to 200 mg / mL, for example about 180 mg / mL of anti-IL-6R antibody.

  In one embodiment, the high concentration anti-IL-6R antibody formulation contains arginine and / or methionine as a stabilizer or excipient in the formulation.

  Since arginine is used in the present invention, any of the arginine compound itself, its derivative and its salt can be used. L-arginine and its salts are preferred. Since methionine is used in the present invention, any of the methionine compound itself, its derivative and its salt can be used. L-methionine and its salts are preferred. When the antibody-containing liquid preparation of the present invention contains arginine but does not contain methionine, the concentration of arginine is preferably 50 to 1500 mM, more preferably 100 to 1000 mM, and even more preferably 200 to 700 mM. When the antibody-containing liquid preparation of the present invention contains arginine and methionine, the total concentration of arginine and methionine is, for example, preferably 50 to 1200 mM, preferably the arginine concentration is 40 to 1000 mM and the methionine concentration is 10 to 200 mM; Preferably, the arginine concentration is 50 to 700 mM and the methionine concentration is 10 to 100 mM; more preferably, the arginine concentration is 100 to 300 mM and the methionine concentration is 10 to 50 mM.

  The buffer solution is prepared using a buffer that is a substance that maintains the pH of the solution. The buffer solution is prepared using a buffer that is a substance that maintains the pH of the solution. The formulation pH of the high concentration antibody-containing liquid formulation of the present invention is preferably 5 to 7, more preferably 5.5 to 6.5, most preferably pH 6. The buffer agent that can be used in the present invention is one that can be adjusted in pH within this range and pharmaceutically acceptable. Such buffering agents are known to those skilled in the art and include, for example, inorganic salts such as phosphate (sodium or potassium) and sodium bicarbonate; citrate (sodium or potassium), sodium acetate and sodium succinate And organic acids such as phosphoric acid, carboxylic acid, citric acid, succinic acid, malic acid and gluconic acid. In addition, Tris buffer, Good's buffer such as MES, MOPS and HEPES, histidine (eg histidine hydrochloride) and glycine can be used. The buffer is preferably a histidine buffer or a glycine buffer, with a histidine buffer being particularly preferred. The concentration of the buffer solution is usually 1 to 500 mM, preferably 5 to 100 mM, more preferably 10 to 20 mM. When using a histidine buffer, the buffer solution preferably contains histidine at a concentration of 5 to 25 mM, more preferably 10 to 20 mM.

The formulation of the present invention may further contain a surfactant. Typical examples of surfactants include nonionic surfactants such as sorbitan fatty acid esters such as sorbitan monocaprylate, sorbitan monolaurate and sorbitan monopalmitate; glycerol monocaprylate, glycerol monomyristate and glycerol Glycerin fatty acid esters such as monostearate; polyglycerol fatty acid esters such as decaglyceryl monostearate, decaglyceryl stearate and decaglyceryl monolinoleate; polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, poly Polyoxy such as oxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan trioleate and polyoxyethylene sorbitan tristearate Tylene sorbitan fatty acid ester; polyoxyethylene sorbitol fatty acid ester such as polyoxyethylene sorbitol tetrastearate and polyoxyethylene sorbitol tetraoleate; polyoxyethylene glyceryl fatty acid ester such as polyoxyethylene glyceryl monostearate; polyethylene glycol distearate Polyethylene glycol fatty acid esters such as polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; polyoxy such as polyoxyethylene polyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propyl ether and polyoxyethylene polyoxypropylene cetyl ether Ethylene polyoxypropylene alkyl ether; Polyoxyethylene alkyl phenyl ethers such as oxyethylene nonyl phenyl ether; polyoxyethylene hydrogenated castor oil such as polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil); polyoxyethylene sorbitol beeswax and the like Polyoxyethylene beeswax derivatives; polyoxyethylene lanolin derivatives such as polyoxyethylene lanolin; HLB 6-18 surfactants such as polyoxyethylene fatty acid amides such as polyoxyethylene octadecanamide; anionic surfactants such as sodium cetyl sulfate And alkyl sulfates having 10 to 18 carbon atoms such as sodium oleyl sulfate; addition ethylene oxide units such as sodium polyoxyethylene lauryl sulfate; Polyoxyethylene alkyl ether sulfate having an average number of moles of 2 to 4 and an alkyl group having 10 to 18 carbon atoms; an alkyl having 8 to 18 carbon atoms such as sulfosuccinate lauryl sodium There are sulfosuccinate salts; natural surfactants such as lecithin and glycerophospholipids; sphingophospholipids such as sphingomyelin; and sucrose esters having 12 to 18 carbon atoms. These surfactants can be added to the formulations of the present invention alone or in combination with more than two of these surfactants.

  Preferred surfactants are polyoxyethylene sorbitan fatty acid esters and polyoxyethylene polyoxypropylene alkyl ethers, particularly preferably polysorbates 20, 21, 40, 60, 65, 80, 81 and 85 and pluronic type surfactants. Most preferred are polysorbates 20 and 80 and Pluronic F-68 (poloxamer 188).

  The amount of the surfactant added to the antibody preparation of the present invention is usually 0.0001 to 10% (w / v), preferably 0.001 to 5%, more preferably 0.005 to 3%.

  In one embodiment, the formulation of the invention comprises (a) an anti-IL-6 receptor antibody; (b) a buffering agent (eg histidine buffer) (c) one or more amino acids (eg arginine and / or methionine) as a stabilizer. And (d) one or more surfactants.

  In one embodiment, the formulation further comprises one or more hyaluronidases (eg, rHuPH20), increasing the dosage of the formulation and / or whole body of a patient whose anti-IL-6R antibody administered subcutaneously is treated with the formulation. In an amount that makes it possible to improve absorption into the bloodstream.

  According to this embodiment of the invention, an anti-IL-6R antibody (eg, tocilizumab) in an amount of about 100 mg / mL to about 300 mg / mL (eg, 180 mg / mL) and about 1,400 to about 1,600 U / mL (eg, A pharmaceutical composition is provided that contains an amount of hyaluronidase enzyme in an amount of about 1,500 U / mL. Preferably, the composition further comprises a buffer (eg, the buffer is histidine, pH 5.5 to 6.5) and / or one or more stabilizers (eg, methionine, arginine and polysorbate).

  The concentration of hyaluronidase enzyme in the formulation is set to an appropriate amount so as to enhance the dispersion and absorption of the co-administered anti-IL-6R antibody. An effective amount of hyaluronidase enzyme is preferably about 1,000 to 16,000 U / ml, corresponding to about 0.01 mg to 0.15 mg of protein based on an estimated specific activity of 100,000 U / mg. A preferred concentration of hyaluronidase enzyme in the formulation is a concentration of about 1,400 U / mL to 1,600 U / mL, more preferably about 1,500 U / mL.

Hyaluronidase enzymes can be derived from animal or human samples or can be made based on recombinant DNA technology. Most preferred is recombinant human PH20 (rhPH20).
Preferably the formulation is isotonic.

IV. Therapeutic uses of anti-IL-6R antibodies In one embodiment, the invention is a method of treating an IL-6 mediated disease in a patient comprising administering an anti-IL-6 receptor (IL-6R) subcutaneously to the patient. Wherein the anti-IL-6R antibody is administered as a fixed dose of 162 mg per dose (eg every week, every 2 weeks or every 10 days).

  Examples of IL-6 mediated diseases treated here include the following diseases: autoimmune diseases, osteoporosis, neoplasms, aging, rheumatoid arthritis (RA), (systemic JIA (sJIA) and articulated JIA Juvenile idiopathic arthritis (including PIA), psoriatic arthritis, Castleman disease, Crohn's disease, multiple myeloma, rheumatoid polymyalgia, glomerulonephritis, plasma cell type or plasmacytosis Myeloma (including multiple myeloma), hyperglobulinemia, anemia, nephritis (such as mesangial proliferative nephritis), cachexia (including cancer cachexia), tumors, T cell mediated diseases (eg Uveitis, chronic thyroiditis, delayed type hypersensitivity, contact dermatitis or atopic dermatitis), lupus (including lupus nephritis and systemic lupus erythematosus), inflammation (including Crohn's disease and ulcerative colitis) Sex intestine Disease, pancreatitis, psoriasis, osteoarthritis, adult stilosis, mesotheliosis, vasculitis, islet transplantation (eg islet transplantation), myocardial infarction (heart failure, ischemia-induced severe arrhythmia), heart transplantation, prostate cancer, Choroidal neovascularization (eg age-related macular neoplasia, idiopathic choroidal neovascularization, myopic choroidal neovascularization, idiopathic choroidal neovascularization), muscle atrophy, chronic rejection, ocular inflammatory disease (eg panuveitis, Anterior uveitis, middle uveitis, scleritis, keratitis, ocular inflammation, optic neuritis, dry eye, diabetic retinopathy, proliferative vitreoretinopathy, postoperative inflammation), graft pair Host disease (GVHD), fibrotic diseases (such as systemic sclerosis), giant cell arteritis (GCA), ankylosing spondylitis and Takayasu arteritis (TA), nodular arteritis.

  In one embodiment, the IL-6 mediated disease is rheumatoid arthritis.

  In one embodiment, the IL-6 mediated disease is juvenile idiopathic arthritis (JIA).

  In one embodiment, the IL-6 mediated disease is systemic JIA (sJIA).

  In one embodiment, the IL-6 mediated disease is articulated JIA (pcJIA).

  In one embodiment, the IL-6 mediated disease is systemic sclerosis.

  In one embodiment, the IL-6 mediated disease is giant cell arteritis (GCA).

  In one embodiment, the IL-6 mediated disease is psoriatic arthritis.

  In one embodiment, the IL-6 mediated disease is uveitis.

  In one embodiment, the patient being treated has rheumatoid arthritis, such patients are insufficient DMARD responders, insufficient TNF inhibitor responders, patients who have not used or discontinued methotrexate (MTX), activity Patients with disease, moderate to severe RA patients and the like are included.

  In one embodiment, the method comprises treating the patient's rheumatoid arthritis by administering tocilizumab subcutaneously to the patient, wherein tocilizumab is administered weekly or every two weeks as a fixed dose of 162 mg per dose. Patients can be treated with the addition of one or more non-biological disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate.

  The present invention also relates to a method of inhibiting the progression of structural joint destruction in rheumatoid arthritis (RA) patients by subcutaneously administering to the patient a fixed dose of 162 mg of anti-IL-6R antibody every 2 weeks. According to this method, structural joint destruction is assessed at 24 weeks (or 6 months) and / or 48 weeks (or 1 year) and compared to patients not treated with anti-IL-6R antibodies (eg, E) The progress is found to be suppressed.

  The present invention further comprises a method of treating an IL-6 mediated disease (such as RA) in a patient comprising administering to the patient an anti-IL-6R antibody (eg, tocilizumab) and a hyaluronidase enzyme (eg, rhPH20), An anti-IL-6R antibody is provided wherein the dose is administered at a fixed dose of 324 mg or 648 mg per dose. Preferably, the fixed dose is administered every 4 weeks or once a month. The anti-IL-6R antibody and hyaluronidase enzyme may be co-prepared or combined into a single pharmaceutical composition and administered subcutaneously to the patient.

  According to the invention, the anti-IL-6R antibody can be administered with a hyaluronidase enzyme such as HuPH20. The final dose of HuPH20 depends on the amount of formulation administered. An exemplary dose range of hyaluronidase to be administered is 1,000 to 10,000 U, for example about 1,350 U, about 2,700 U or about 5,400 U. For example, 1,350 U HuPH20 is administered at 0.9 mL, 2,700 U HuPH20 at 1.8 mL, or 5,400 U HuPH20 at 3.6 mL. The anti-IL-6R antibody and hyaluronidase enzyme can be administered simultaneously or sequentially in the same or different formulations. Preferably the antibody and enzyme are co-prepared and administered simultaneously, eg, via a single SC administration device.

  In one embodiment, an anti-IL-6R antibody (eg, tocilizumab) is administered subcutaneously to a juvenile idiopathic arthritis (JIA) patient in an amount effective for JIA treatment.

  In one embodiment, the patient has systemic JIA (sJIA). Such sJIA patients have 162 mg of antibody (eg, tocilizumab) every week if the patient weight ≧ 30 kilograms, and 162 mg of antibody (eg, tocilizumab) every 10 days (± 1 day) if the patient weight <30 kilograms. Can be treated. In an alternative embodiment, sJIA patients weighing <30 kilograms are treated with 162 mg of antibody (eg, tocilizumab) weekly or every two weeks. In yet another embodiment, sJIA patients weighing <30 kilograms are treated with 108 mg of antibody (eg, tocilizumab) weekly.

  In another embodiment, the patient has articulated (pcJIA). Such patients can be treated with 162 mg of antibody (eg tocilizumab) every two weeks.

  In another embodiment, the anti-IL-6R antibody is administered subcutaneously to a fibrotic patient (such as systemic sclerosis) in an amount effective to treat the fibrotic disease. If the disease is systemic sclerosis, it improves skin sclerosis (e.g., assessed by a modified Rodnan skin score (mRSS)), improves physical function (e.g., scleroderma) compared to placebo. Dysfunction index using a health assessment questionnaire (HAQ-DI)) and / or delayed progression of organ destruction. For the treatment of fibrotic diseases such as systemic sclerosis, the antibody (eg tocilizumab) may be administered as a fixed dose of 162 mg per dose, eg every week or every two weeks.

  In another embodiment, the anti-IL-6R antibody is administered subcutaneously in an amount effective for CGA treatment to treat giant cell arteritis (GCA). The antibody can be administered to GCA patients as a fixed dose of 162 mg per dose (eg, every week or every two weeks). GCA patients can also be treated with corticosteroids for the first (short) course. Such treatment of GCA may reduce signs and symptoms of GCA, maintain clinical remission, and / or reduce or discontinue corticosteroid use in GCA patients. The GCA herein optionally includes new-onset GCA and refractory GCA in adult patients.

  In one embodiment of all methods herein, no medicament other than an anti-IL-6R antibody (optionally co-prepared with a hyaluronidase enzyme) is administered to a subject to be treated for an IL-6 mediated disease.

  In another embodiment of any of the methods herein, an additional effective amount or drugs to treat the disease may be administered with the anti-IL-6R antibody. The additional drug may be one or more medicaments, such as immunosuppressants, non-steroidal anti-inflammatory drugs (NSAIDs), disease modifying anti-rheumatic drugs (DMARD), methotrexate (MTX), anti-B cells Surface marker antibodies, anti-CD20 antibodies, rituximab, TNF inhibitors, corticosteroids and costimulatory modulators, or any combination thereof.

Examples of such additional drugs include: immunosuppressants (such as mitoxantrone (Novantrone®), methotrexate, cyclophosphamide, chlorambucil, leflunomide and azathioprine), intravenous Immunoglobulin (gamma globulin), lymphocyte depletion therapy (eg mitoxantrone, cyclophosphamide, CAMPATH ^™ antibody, anti-CD4, cladribine, de-immunized specifically identified by Ig receptors on autoreactive B cells Polypeptide constructs having at least two domains with self-reactive antigens or fragments thereof (WO 2003/68822), whole body irradiation, bone marrow transplantation), integrin antagonists or antibodies (eg efalizumab commercially available from Genentech) / Laptiva (registered trademark) LFA-1 antibodies such as, or alpha4 integrin antibodies such as natalizumab / ANTEGREN® commercially available from Biogen, or the like, steroids such as corticosteroids (eg prednisolone, SOLU-MEDROL for injection ( ® methylprednisolone such as methylprednisolone sodium succinate, prednisone such as low-dose prednisone, dexamethasone or glucocorticoid, including systemic corticosteroid treatment, eg by joint injection, non-lymphocyte depletion immunosuppressive treatment (eg MMF) Or cyclosporine), “statin” class cholesterol-lowering drugs (cerivastatin (Vaicol ^™ ), fluvastatin (Rescol ^™ ), atorvastatin (Lipitor ^™ ), lovastatin ( Mevacor ^TM), including pravastatin (pravachol ^TM) and simvastatin (Zocor ^TM)), estradiol, testosterone (optionally extenders; Stuve et al Neurology 8: 290-301 (2002)) , androgen, hormone replacement therapy, for TNF- alpha TNF inhibitors such as antibodies, DMARD, NSAID, plasmapheresis or plasma exchange therapy, trimethoprim sulfamethoxazole combination (Bactrim ^™ , Septra ^™ ), mycophenolate mofetil, H2 blocker or proton pump inhibitor (latent Ulcerogenic immunosuppressive therapy in use), levothyroxine, cyclosporin A (eg Sandimune®), somatastatin analog, DMARD or NSAID, cytokine antagonists such as antibodies, antimetabolites B containing an immunosuppressant, rehabilitation surgery, radioiodine, thyroidectomy, BAFF antagonist such as BAFF or BR3 antibody or immunoadhesin, anti-CD40 receptor or anti-CD40 ligand (CD154), anti-CD20 antibody such as rituximab or ofatumumab Cell antagonists or antibodies; IL-1 blockers such as rHUIIL-1Ra (Anakira, Amgen-Synergen) and thiaprofenic acid I-1B inhibitor (Hoechst); and CTLA-4-Ig fusion protein Orencia® (Abatacept) ( Costimulatory modifiers such as Bristol-Myers Squibb; Enrilomab (anti-ICAM-1 monoclonal antibody); CDO-855 (humanized antibody that binds specifically to a region of the class II MHC complex, Celltech); CH-3298 (Chiroscience); GW353430 (anti-CD23 monoclonal antibody, Glaxo Wellcome); GR252025 (COX02 inhibitor, Glaxo Wellcome); 4162W94 (anti-CD4 humanized antibody; Glaxo Wellcome); azathioprine (DMARD, Glaxo Welcome); penicillamine and phenopro Fen (Eli Lilly);

  The second or additional drug may be selected from the group consisting of non-biological DMARDs, NSAIDs and corticosteroids.

  These additional drugs described in the present invention are usually used in the doses and routes of administration described above, or are used at doses of about 1 to 99% of the doses used so far. When such an additional drug is used, it is preferably used at a lower dose than in the absence of the first drug, particularly in administration after the first administration including the first drug, and side effects due to its use. Is eliminated or reduced.

  Co-administration of additional drugs includes co-administration (concurrent administration) using separate or single pharmaceutical formulations and sequential administration in any order, preferably both (or all) activities There is time for the agent (medicine) to exert its biological activity simultaneously.

  In one embodiment, the patient can be treated with an IV administered anti-IL-6R antibody before or after administration of the SC dose.

V. Articles of Manufacture In another embodiment of the invention, an article of manufacture containing materials useful for the treatment of the aforementioned IL-6 mediated diseases is provided. The invention specifically provides an article of manufacture comprising a subcutaneous administration device that delivers a fixed dose of anti-IL-6 receptor (IL-6R) antibody to a patient, where the fixed dose is 162 mg, 324 mg and 648 mg of anti-IL- Selected from the group consisting of 6R antibodies. Preferably the anti-IL-6R antibody is tocilizumab. Preferably, the antibody concentration in the device is 150 to 200 mg / mL, such as 180 mg / mL. The antibody in the syringe is preferably formulated in a buffer (eg, histidine, pH 6) and other excipients (methionine, arginine and polysorbate) so that it becomes a stable pharmaceutical formulation in the syringe. Hyaluronidase, such as rHuPH20, may be included in the formulation in an amount of, for example, about 1,400 U / mL to about 1,600 U / mL (eg, about 1,500 U / mL). The device can deliver 0.9 mL, 1.8 mL, or 3.6 mL of formulation to the subject.

Suitable devices SC delivery (including prefilled syringes) syringe; (devices such as, for example, INJECT-EASE ^TM and GENJECT ^TM) syringe; infusion pump (e.g. Accu-Chek ^TM); injection pen (GENPEN ^TM, etc.); non Needle devices (eg MEDDECTOR ^™ and BIOJECTOR ^™ ); automatic injectors, subcutaneous patch delivery systems, and the like.

  The article of manufacture may further include a package insert that includes instructions for treating an IL-6 mediated disease (eg, RA) in the subject, wherein the instructions for use are treated with the antibodies described herein. It represents treating -6 mediated diseases and being able to inhibit the progression of structural joint destruction (eg in RA patients).

  Further details of the invention are illustrated in the following non-limiting examples. The disclosures of all citations herein are expressly incorporated herein by reference.

Example 1
Clinical Trial to Determine Fixed Dose of Anti-IL-6R Antibody Subcutaneous (SC) Weekly subcutaneously administered (SC QW) 162 mg of anti-IL-6R antibody (Tocilizumab, TCZ) is a Phase 1 study in healthy subjects ( WP18097 and BP22065), Phase 1 study in Japanese RA patients (MRA227) and Phase 1 study in white RA patients (NP22623) included Phase 1/2 study. Further details of these SC tests and the 4 tests that obtained comparative data are shown in Table 1.

  In these studies, a TCZ formulation with 180 mg / mL TCZ but no hyaluronidase was used (see Table 2 in Example 4).

  In the Japanese RA trial MRA227, all patients (32) were randomly assigned to any of the three trial arms: 81 mg SC Q2W / QW, 162 mg SC Q2W and 162 mg SC QW. In the Caucasian RA trial NP22623, all 29 patients were randomly assigned to either of the two treatment arms: 162 mg SC Q2W (N = 15) and 162 mg SC QW (N = 14).

  A dose basis was constructed based on observational data from two trials of RA patients.

The choice of this 162 mg QW dosage regimen was derived from three main factors:
The sIL-6R binding TCZ complex (PD biomarker of TCZ mechanism of action; Nishimoto et al., Blood 112 (10): 3959-3964 (2008)) is faster and faster at 162 mg QW compared to other test SC dose regimens. Increase significantly (Fig. 1).
CRP decreases faster and consistently at 162 mg QW compared to other test SC dose regimens (FIG. 2).
The safety profile of SC treatment arms is not considered different from each other or from 8 mg / kg IV Q4W.
In general, the study SC dose regimen is well tolerated in the MRA 227 and NP22623 studies.
Of note, there was no death in the SC treatment arm and there was only one SAE (pyelonephritis).
Since the mean exposure (AUC, C _max ) of 8 mg / kg IV Q4W is generally higher than any SC dosage regimen, the safety profile of 162 mg QW is considered equivalent to that of 8 mg / kg IV (FIG. 4).

sIL-6R
FIG. 1 shows the sIL-6R profile after SC and IV regimens. The sIL-6R profile of RA patients receiving 162 mg QW closely resembles that observed with 8 mg / kg IV Q4W in the rate and magnitude of elevation. Other test dose regimens (81 mg Q2W / QW or 162 mg Q2W) did not reach levels comparable to 8 mg / kg IV Q4W.

CRP
FIG. 2 shows the CRP profile after 162 mg SC QW and 8 mg / kg IV Q4W dose regimen for RA patients. 162 mg QW showed the fastest and lasting reduction in CRP concentration among the test SC dose regimens.

DAS28-ESR
Disease activity (measured with DAS28-ESR) is thought to be faster and significantly reduced from baseline in 162 mg SC QW compared to other study SC dose regimens (FIG. 3).

Safety: Observational Data There were no deaths in 4 trials of TCZ SC, and only one SAE (81 mg dose group pyelonephritis) was reported. The AEs observed after single or repeated SC administration of healthy or RA patients were generally consistent with the type and severity of AEs observed in the Phase 3 RA IV trial. The NP22623 data did not show a different AE profile between the 162 mg QW and Q2W dose groups. The mean change in laboratory measurements of Japanese RA patients and Caucasian RA patients undergoing SC TCZ was similar to that of IV patients with RA. One Japanese RA patient who received 162 mg QW showed neutropenia and the dose was reduced to 162 mg Q2W. One patient receiving 81 mg Q2W showed neutropenia, and no subsequent administration was performed when switching to 81 mg QW in the 11th week. SC injections were generally well tolerated. SC injections were not recognized as more painful than subcutaneous placebo injections.

  In the MRA 227 study, none of the 162 mg QW group patients were anti-TCZ antibody positive. 4 patients in the low dose group were positive for anti-TCZ antibody (all in 81 mg QW / Q2W dose group, 1 before TCZ administration); 5 were positive for anti-TCZ IgE antibody (3 patients in 81 mg Q2W / QW dose group and 162 mg Q2W dose group 2 patients). Among patients who tested positive in antibody tests, one patient who was positive at baseline had grade 1 eczema but was considered unrelated (food allergy), and one patient had grade 1 urticaria And another patient had a bruise at the injection site. No other AEs in the “skin and subcutaneous tissue” and “systemic disorders and local mode of administration” classes of patients who tested positive for anti-TCZ antibodies were reported.

PK-safety relationship Visually verifying the steady state PK profiles between the SC and IV regimens in the MRA 227 and LRO301 trials, respectively, the 8 mg / kg IV regimen is generally more exposed than the 162 mg QW SC regimen. (Average AUC, C _max ) (FIG. 4). The exception is the mean C _trough , with the 162 mg QW regimen being more concentrated than 8 mg / kg IV (26 ± 15 μg / mL at week 15 and 16 ± 11 μg / mL at week 16). The other low dose groups did not reach a concentration equivalent to 8 mg / kg IV at steady state. There was a large variation (58%) among subjects with C _trough of the 162 mg SC regimen. The safety profile of 162 mg SC QW is expected to be similar to that of 8 mg / kg IV Q4W since the 8 mg / kg IV Q4W dose regimen is generally higher exposure than any SC dose regimen.

A single fixed dose (162 mg QW dose) is administered to all RA patients regardless of body weight. This approach shows that the highest exposures of all three categories (C _max , C _trough and AUC) of the 162 mg QW dosage regimen observed are within the scope of the IV program, even after subtracting exposure differences that may be due to overall body weight for fixed doses. Supported by the fact that

  In addition, this approach is supported by IV program safety data analysis (SAE, AE, clinical laboratory). There is no clear relationship between TCZ exposure and the occurrence of class-specific adverse events, especially the most frequent adverse events of the “infection and parasitic disease” and “skin and subcutaneous tissue” classes. There is no clear relationship between TCZ exposure and serious adverse events. With increasing exposure, there was no apparent increase in the frequency of abnormal laboratory results other than neutropenia. A slightly higher rate of Grade 3 or higher neutropenic events was observed in TCZ high exposure category patients. In addition, there was one grade 3 thrombocytopenia event in the TCZ high exposure category. Concerning triglyceride, total cholesterol and LDL cholesterol levels, a slightly higher rate was observed in TCZ high exposure category patients. Taken together, these data suggest that the use of a fixed dose regimen is acceptable.

  In summary, the 162 mg SC QW dosage regimen was selected based on the following: 1) 162 mg SC QW sIL-6R binding TCZ complex increased faster and significantly at 162 mg SC QW, and 8 mg of the test dosage regimen / Kg IV Q4W was most similar; 2) CRP decreased consistently faster with 162 mg SC QW than other study SC dosage regimens: 3) The safety profile of SC treatment arms It appears that there is no difference from 8 mg / kg IV Q4W; and 4) The safety profile of 162 mg SC QW is 8 mg / kg IV because the total exposure of 8 mg / kg IV Q4W is generally higher than any of the study SC dose regimens. It should be similar to Q4W.

Example 2
RA clinical trial of SC anti-IL-6 receptor antibody for moderate to severe active RA patients who are currently poorly responsive to a stable dose of DMARD that may contain one or more anti-TNF biologics. Phase III, 2-arm, 2-year, randomized, double-blind, double-dummy, active-control parallel group, multicenter collaborative study. The primary endpoint is evaluated at week 24. The overall design of this example is shown in FIG. The formulation is as in Example 1.

  Screening visits can occur up to 21 days prior to the baseline randomized visit (or up to 56 days if longer than 21 days are required for no treatment). Patient eligibility is determined at screening and baseline visits, at which time patients are randomized. The number of patients who have failed past anti-TNF treatment will be limited to about 20% of the total population.

Exam participation criteria
1. Age ≧ 18 years old Rheumatoid arthritis period ≥ 6 months, diagnosed according to the classification criteria of the 1987 Revised American College of Rheumatology (ACR, former American Association of Rheumatology).
3. Number of expanded joints at screening and baseline (SJC) ≧ 4 (66 joints) and tender joints (TJC) ≧ 4 (68 joints).
4). Prior to randomization, etanercept was discontinued for ≧ 2 weeks, infliximab, certolizumab, golimumab, abatacept or adalimumab for ≧ 8 weeks, and anakinra for ≧ 1 week.
5. Prior to baseline, he received an acceptable stable dose of DMARD for at least 8 weeks.
6). At the time of screening, CRP ≧ 1 mg / dL (10 mg / L) or ESR ≧ 28 mm / hr.
7). Oral corticosteroids (≦ 10 mg / day prednisone or equivalent) and NSAIDs (up to the highest recommended dose) are acceptable when on a ≧ 4 week stable dose regimen prior to baseline.

  During the double-blind period, at baseline visit, patients will receive either a 1: 1 ratio of TCZ162 mg SC weekly and placebo IV Q4W (Group A), or TCZ 8 mg / kg IV Q4W and placebo SC QW (Group B). Randomized and treated for 24 weeks. The primary analysis is performed when all patients have reached week 24.

At week 24, all patients are randomized again for the open-label period as follows:
Group A: Patients are randomized again at a ratio of 11: 1 and receive TCZ162 mg SC weekly (Group A1) or 8 mg / kg IV every 4 weeks (Group A2).
Group B: Patients are randomized again at a 2: 1 ratio and receive 8 mg / kg IV every 4 weeks (Group B1) or TCZ 162 mg weekly (Group B2) at SC.

  Prior to the first drug administration of a double-blind study (baseline visit), patient outcomes and efficacy assessments should be made within 24 hours (allowed up to 72 hours as needed). A week-long drug holiday is placed between weeks 24 and 25, and the first treatment in the open-label period is performed in week 25.

  Efficacy parameters are assessed at baseline, weeks 2, 4 and then every 4 weeks up to week 24, then weeks 37, 49, 73, 97, or early dropout (WD) visits.

  Each treatment group is allowed background treatment using non-biological DMARDs, corticosteroids and / or NSAIDs initiated prior to TCZ administration. The dose of NSAID, corticosteroid and / or non-biological DMARD must be constant during the core study period (up to week 24). However, doses may be reduced in these treatments if necessary for safety reasons.

Efficacy evaluation ACR20
The American College of Rheumatology (ACR) outcome criteria core set and definition of improvement includes both SJC and TJC, and an additional five parameters (general assessment of disease activity by physicians, general assessment of disease activity by patients) , Patient pain assessment, HAQ and acute phase response (CRP or ESR)) include> 20% improvement over baseline.

  ACR50 acquisition requires ≧ 50% improvement with the same parameters, and ACR70 requires ≧ 70% improvement.

Disease Activity Score 28 (DAS28) -ESR
DAS28 is a composite index that measures RA disease activity. This index includes dilation and tender joint counts, acute phase response (ESR or CRP) and general health status. In this study, ESR is used to calculate the DAS28 score. The index is calculated using the following formula: DAS28 = 0.56 × √ (TJC28) + 0.28 × √ (SJC28) + 0.36 × ln (ESR + 1) + 0.014 × GH + 0.96
Where TJC28 is the number of tender joints of 28 joints, SJC28 is the number of expanded joints of 28 joints, ln is the natural logarithm, ESR is the erythrocyte sedimentation rate (mm / hr) and GH is the general health condition, ie the disease activity by the patient Overall rating (100-mm VAS). The DAS28 scale ranges from 0 to 10, with a high score indicating high disease activity.

ACR-Hybrid ACR-Hybrid is a measurement that combines the percent improvement in ACR core parameters with the status of ACR20, ACR50 or ACR70.

  The weekly subcutaneously administered (SC) TCZ 162 mg treatment disclosed in this example is comparable to TCZ 8 mg / kg administered intravenously (IV) every 4 weeks based on any one or more of the above efficacy criteria. Expected to be safe and effective.

Example 3
Anti-IL-6R antibody SC that suppresses progression of joint destruction
This is a phase 3, 2 arm, 2 year, randomized, dual, for moderate to severe active RA patients currently unresponsive to DMARD that may contain one or more anti-TNF-α agents. This is a blinded, placebo-controlled parallel multicenter study. The primary endpoint is evaluated at week 24.

  The overall design is shown in FIG. Screening visits can occur up to 21 days prior to the baseline randomized visit (or up to 56 days if longer than 21 days are required for no treatment). Patient eligibility is determined at screening and baseline visits. Randomize patients at baseline. The number of patients who failed previous anti-TNF-α treatment would be limited to about 20% of the total population. The formulation is as in Example 1. The formulation is administered using a prefilled syringe (PFS) or an automatic injector (AI).

TCZ Q2W Administration In this study, TCZ 162 mg is administered every two weeks (Q2W) instead of weekly (QW). Compared to the response with 162 mg SC QW, 162 mg SC Q2W increased sIL-6R binding TCZ complex and acquired CRP normalization, as described below, resulting in DAS-ESR from baseline. It is considered to be a low-dose SC option that decreases. Furthermore, the PD response and preliminary efficacy measures of the 162 mg SC Q2W regimen are superior to the other study low dose regimens (81 mg Q2W / QW).
SIL-6R complex, a PD biomarker of TCZ mechanism of action, is less increased at 162 mg SC Q2W than 162 mg SC QW, but significantly increased compared to other low dose SC regimens (81 mg Q2W / QW) ( FIG. 1).
CRP normalization is obtained with 162 mg SC Q2W; the low dose SC regimen did not result in CRP normalization (FIG. 2).
The disease activity score DAS28-ECR is expected to be significantly reduced from baseline at 162 mg SC QW and 162 mg SC Q2W compared to other study SC dose regimens (81 mg SC Q2W / QW) (FIG. 3).

safety:
Based on the available safety observation data, the safety profile of the SC treatment arms is considered to be no different from each other or from the IV program.
162 mg SC QW and Q2W were well tolerated in the MRA 227 and NP22623 studies.
There was no death in any SC treatment arm. One case of pyelonephritis occurred as SAE in the 81 mg SC dose group.
Since the mean exposure (AUC, C _max , C _trough ) is generally higher for the 8 mg / kg IV dose than the 162 mg SC Q2W, the safety profile of 162 mg SC Q2W appears to be comparable to the IV program (FIG. 4). ).

sIL-6R complex The sIL-6R binding TCZ complex is a PD biomarker of the mechanism of action of TCZ. FIG. 1 shows the sIL-6R profile after SC and IV regimens. The sIL-6R profile of RA patients receiving 162 mg SC QW is very similar to that observed at 8 mg / kg IV q4w in both rate and width of elevation. Other test dose regimens (81 mg Q2W / QW and 162 mg Q2W) did not reach concentrations comparable to 8 mg / kg IV q4w. The biweekly (Q2W) 162 mg dose showed lower responsiveness than observed with 162 mg QW and 8 mg / kg IV. The sIL-6R complex is significantly increased at 162 mg SC Q2W over other test low dose SC regimens and 4 mg / kg IV.

CRP
FIG. 2 shows the CRP profile after SC and IV dose regimen for RA patients. 162 mg SC QW had the fastest and lasting decrease in CRP concentration among the tested SC dose regimens. Of the low-dose SC regimen, 162 mg SC Q2W reached normalization (note that MRA227 patients were given a single dose (SD) at week 0, then repeated dosing was started at week 3; 81 mg Q2W was switched to QW in the ninth week (see FIG. 2). A lower dose SC regimen (81 mg QW / Q2W) was considered unable to achieve CRP normalization. Therefore, 162 mg SC Q2W is considered to be a low dose SC option that can provide CRP normalization.

DAS28-ESR
FIG. 3 shows changes in DAS28-ESR after SC and IV dose regimens in RA patients. DAS28-ESR data for the SC regimen is limited, but disease activity declined faster and significantly from baseline at 162 mg SC QW and 162 mg SC Q2W than other study SC dose regimens (81 mg SC Q2W / QW) (Figure 3). Compared to the response observed with 162 mg SC QW, 162 mg SC Q2W is considered to be a low dose SC dose option that obtains a reduction in DAS-ESR from baseline.

PK & PK-safety relationship Average exposure (AUC, C _max , C _trough ) after repeated TCZ administration (MRA227) to RA patients is 4 mg / kg IV q4w C _trough lower than C _trough observed with 162 mg SC Q2W Except for concentrations, the 4 & 8 mg / kg IV q4w dose is generally higher than the 162 mg SC Q2W (FIG. 4). The safety profile of the IV program has been extensively tested. From these summaries and a comparison with 162 mg SC QW, the 162 mg SC Q2W dose is considered to be a low dose SC dose option with an acceptable safety profile based on drug exposure.

Mean exposure (AUC, C _max , C _trough ) was generally 162 mg SC Q2W for 4 & 8 mg / kg IV q4w doses, except for the C _trough concentration of 4 mg / kg IV q4w, which is lower than the C _trough observed with 162 mg SC Q2W. Higher (Figure 4). The safety profile of the IV program has been extensively tested. From these summaries and a comparison with 162 mg SC QW, the 162 mg SC Q2W dose is considered to be a low dose SC dose option with an acceptable safety profile based on drug exposure.

A single fixed dose (162 mg SC Q2W and 162 mg SC QW for escape treatment) is administered to all RA patients regardless of body weight. This approach is the highest exposure defined by the three parameters of the observed 162 mg SC QW and Q2W dose regimens (C _max , C _trough and AUC), subtracting the difference in exposure that can be attributed to the full range of body weight for a fixed dose. Is supported by the fact that it is within the scope of the IV program. In addition, this approach is supported by IV program safety data analysis (SAE, AE, laboratory). There is no clear relationship between TCZ exposure and the occurrence of class-specific adverse events, especially the most frequent adverse events of the “infection and parasitic disease” and “skin and subcutaneous tissue” classes. There is no clear relationship between TCZ exposure and serious adverse events. Other than neutropenia, there was no obvious increase in the frequency of laboratory abnormalities associated with increased exposure. A slightly higher rate of Grade 3 or higher neutropenic events was observed in TCZ high exposure category patients. In addition, there was a single grade 3 thrombocytopenic event in the TCZ high exposure category. Concerning triglyceride, total cholesterol and LDL cholesterol levels, a slightly higher rate was observed in TCZ high exposure category patients. Taken together, these data suggest that the use of a fixed dose regimen is acceptable. The effect of body weight on PK will be further evaluated in this study.

Safety data observed in RA patient SC trial (MRA227 and NP22623)
All (32) patients participated in the MRA227 study, 29 patients participated in the NP22623 study, and received TCZ SC treatment including 81 mg QW / Q2W (MRA227 only), 162 mg Q2W and 162 mg QW. Subcutaneous tolerability of RA patients was good up to 33 weeks in the MRA227 study and up to 12 weeks in the NP22623 study. The AE observed after SC dose administration to RA patients was generally consistent with the type and severity of those observed in the TCZ IV phase 3 trial.

  No deaths were reported in 4 SC TCZ trials. One SAE of pyelonephritis was reported in the 81 mg dose group. Limited data for NP22623 did not show different AE profiles between the 162 mg SC QW and Q2W dose groups. The magnitude of the mean change in measurements for Japanese RA patients and Caucasian RA patients who received SC TCZ were both similar to those of RA patients in the IV program. The 162 mg SC QW Japanese RA dose was reduced to 162 mg SC Q2W. One patient receiving 81 mg SC Q2W showed neutropenia and no further doses were administered at week 11. SC TCZ injection was generally well tolerated and was not recognized as more painful than subcutaneous placebo injection.

  In the MRA 227 study, there were no anti-TCZ antibody positive patients in the 162 mg QW group. 4 patients in the low dose group were anti-TCZ antibody positive (all patients in 81 mg QW / Q2W dose group, 1 before TCZ administration); 5 patients were positive in anti-TCZ IgE antibody (81 mg Q2W / QW dose group) 3 patients and 2 patients in the 162 mg Q2W dose group). Among patients who tested positive for antibody, Grade 1 eczema was observed in one patient who was positive at baseline, but was considered unrelated (food allergy), and one patient had Grade 1 urticaria Another patient had a bruise at the injection site. No other AEs in the “skin and subcutaneous tissue” and “systemic disorders and local mode of administration” classes of patients who tested positive for anti-TCZ antibodies were reported. In NP22623, 3 patients were positive for anti-TCZ antibody in the screening assay, but no patient was positive in the confirmation assay.

Summary Previously, TCZ 162 mg SC weekly (QW) was selected as the comparator dose regimen of TCZ 8 mg / kg IV q4w. The observational data on PK, PD, efficacy and safety of RA patients with remaining study SC doses of RA indicate that 162 mg SC biweekly (Q2W) is an appropriate low dose SC dose option for this NA25220B study.

  At the baseline visit, patients will be randomized to either TCZ162 mg SC Q2 (Group A) or placebo SC QW (Group B) at a 2: 1 ratio and will be treated for 24 weeks. A primary analysis is performed when all patients reach week 24.

  From the 24th week, all patients will receive open-label treatment with TCZ162 mg SC Q2W and no patients will receive a placebo injection.

In addition, at the 24th week visit, patients will be randomized again for an open-label period as follows:
Group A: Patients are randomized again at a 1: 1 ratio and TCZ162 mg SC biweekly using an automatic injector (AI) (Group A1) or using a prefilled syringe (PFS) (Group A2) receive.
Group B: Patients are randomized again at a 1: 1 ratio and receive TCZ162 mg SC biweekly using AI (Group B1) or using PFS (Group B2).

  Prior to the first drug administration in a double-blind study (baseline visit), patient outcomes and efficacy assessments should be made within 24 hours (allowed up to 72 hours as needed).

  Efficacy parameters are assessed at baseline, week 2, week 4, and every 4 weeks thereafter until week 40, then at weeks 48, 60, 72, 84, 96, or at the early dropout (WD) visit.

  X-rays of each hand and foot are taken at the 24th and 48th week screening.

Treatment groups Individual treatment groups:
Group A: ~ 400 (number of patients), TCZ162 mg SC Q2W, PFS use during 24 weeks double-blind period, then randomized again below:
Group A1: ~ 200 (number of patients), TCZ162mg SC q2w, AI used during the open-label period Group A2: ~ 200 (number of patients), TCZ162mg SC q2w, PFS used during the open-label period B group: ~ 200 (Number of patients), placebo SC Q2W, PFS use during the 24-week double-blind period, then randomized again to:
Group B1: ~ 100 (number of patients), TCZ162mg SC q2w, AI used during open-label period Group B2: ~ 100 (number of patients), TCZ162mg SC q2w, used PFS during open-label period

  Patients, facility staff, and sponsors are in a double-blind period until all patients have completed the double-blind treatment period at week 24, and all patient data up to this point has been collected, locked, and reported. I do not know whether TCZ or placebo was administered.

  Each treatment group is required to receive a background treatment of non-biological DMARD that began administration at a fixed dose 8 weeks prior to the first dose of TCZ. The dose of non-biological DMARD and corticosteroid should be constant during the core study (up to week 248). The dose of NSAID should be constant until week 24. However, for safety reasons, weight loss in these treatments is allowed. Patients can also receive an increase in intra-articular steroid and / or oral corticosteroid doses (the highest dose is a total of 10 mg dose / day).

Primary and secondary study endpoints Primary endpoint The primary endpoint is the proportion of ACR20 responding patients at week 24.
Secondary endpoints All secondary endpoints are formally tested, except for changes in the van der Heijde modified Sharp radiographic score from baseline to week 48. To maintain the alpha level at 5%, secondary endpoints are tested using a pre-specified fixed order method. This method is detailed in DAP.
1. From the base line ^* van der Heijde modified Sharp X-ray score of up to 24 weeks.
2. From the base line ^* van der Heijde modified Sharp X-ray score of up to 48 weeks.
3. Percentage of patients with ACR50 response at week 24.
4). Percentage of patients with ACR70 response at week 24.
5. Mean change in week 24 from baseline in individual parameters of the ACR core set.
6). Main clinical response at week 48 (ACR70 response is maintained beyond 24 weeks of treatment).
7). Change in disease activity score (DAS28) from baseline at week 24.
8). Change in HAQ-DI from baseline at week 24.
9. Percentage of patients classified as clearly having a DAS28 response (EULAR response) at week 24.
10. Percentage of patients who acquired DAS28 low disease activity (DAS ≦ 3.2) at week 24.
11. Percentage of patients with HAQ change ≧ 0.3 from baseline at week 24.
12 Percentage of patients with DAS28 score <2.6 at week 24 (DAS remission).
13. Change in SF-36 subscale and summary score at week 24.
14 At start of treatment group ACR 20, 50, 70.
15. Change in hemoglobin concentration from baseline at week 24.
* Assessment taken before the first dose of study drug is considered the baseline.

X-ray assessment At the 24th and 48th week screenings, X-rays of each hand (back-front, PA) and foot (front-back, AP) are taken separately. X-rays are taken using the van der Heijde correction method by Sharp (van der Heijde, D. "How to read radiographs according to the Sharp / van der Heijde method." J Rheumatol 27: 261-263 (2000)). evaluate.

  All non-escape patients will receive TCZ SC Q2W from the 24th week. Week 48 x-ray analysis compares patients randomized to placebo at baseline with patients randomized to TCZ SC Q2W, both groups taking the drug from week 24 . Verify whether the rate of progress of structural destruction is different between the two periods. This is particularly relevant for groups randomized to placebo at baseline.

  The SC anti-IL-6R antibody (TCZ) and DMARD combination therapy disclosed in this example is expected to be effective (based on Week 24 ACR20 data) and safe (with respect to AE and laboratory findings). Furthermore, SC anti-IL-6R antibody (TCZ) treatment can suppress the progression of structural joint disease at weeks 24 and 48 and can improve the physical function of RA patients.

Example 4
Hyaluronidase enzyme-containing anti-IL-6R antibody composition This example describes the development of a stable pharmaceutical formulation containing an anti-IL-6R antibody (tocilizumab) and a hyaluronidase enzyme (recombinant human PH20, rHuPH20).

The active anti-IL-6R antibody tocilizumab (see, eg, US Pat. No. 5,795,965) is the active ingredient in the formulation and is used to treat RA or other IL-6 mediated diseases.

  Recombinant human PH20 (rHuPH20) (see, eg, US Pat. No. 7,767,429) is included to increase the dispersion of SC-injected TCZ, allowing SC injections in quantities greater than 2 mL and without hyaluronidase. Potentially increases bioavailability compared to the formulation (see Example 5).

pH / Buffer Selection The pH that stabilizes 162 mg of tocilizumab SC vial was found to be approximately pH 6.0. Therefore, pH 6.0 ± 0.5 was chosen for this formulation. L-histidine / L-histidine monohydrochloride is added to the formulation as a buffer at a concentration of 20 mM, which is within the normal concentration range of 10-100 mM for parenteral buffers. A pH of approximately 6.0 is obtained using a predetermined ratio of buffer salt and base, but may optionally be adjusted using sodium hydroxide or hydrochloric acid.

Stabilizer Polysorbate 80 is added as a stabilizer at a concentration of 0.2 mg / mL to prevent protein destabilization due to mechanical stress (stirring) and potential freezing / thawing.

  L-arginine hydrochloride and L-methionine are added as stabilizers at concentrations of 100 mM and 30 mM to prevent protein destabilization due to heat stress.

Formulation development The goal was to develop a stable sterile liquid solution for subcutaneous injection of tocilizumab.

  The SC formulation was developed in consideration of the effect of protein concentration on the release power and viscosity of a standard syringe because the concentration of tocilizumab used was as high as 180 mg / mL compared to 20 mg / mL of the IV formulation. The volume of subcutaneous injection is ideally less than 1 mL and the formulation requires a high concentration of protein. On the other hand, high viscosity due to high concentration of protein increases injection power. From the correlation between protein concentration and viscosity, the target tocilizumab concentration was 180 mg / mL.

Table 2 is a comparison of an exemplary tocilizumab SC formulation and a tocilizumab IV formulation. A lyophilized SC formulation containing 114.3 mg / mL TCZ was used in a previous human pharmacokinetic clinical study conducted in France using 20 healthy individuals. The purpose of the study was to verify the absolute bioavailability and tolerability of the subcutaneous route of administration.

Overdose Do not use overdose in the formulation.

Hyaluronidase enzyme-containing formulations The following table summarizes the ingredients and their concentrations in an exemplary formulation containing both anti-IL-6R antibody (TCZ) and hyaluronidase (rHuPH20):

Physicochemical / biological properties The formulation showed good stability under the recommended storage conditions of 2-8 ° C. protected from light.

PK trials Two nonclinical PK trials were conducted using hyaluronidase-containing TCZ SC formulations, one in minipigs and the other in cynomolgus monkeys (Table 4):

  The reason for choosing minipigs for rHuPH20 dose selection is that the skin and SC tissue texture is believed to be similar to that of humans. In the minipig study, absolute bioavailability / absorption rates were evaluated using two SC dose levels of TCZ formulations containing various concentrations of rHuPH20 as well as the TCZ alone IV administration arm (Table 4). As a result of the test, SC administered TCZ was absorbed faster from the rHuPH20 containing formulation. Thus, the median time to maximum plasma concentration of TCZ was reduced from 48 hours for the rHuPH20-free formulation to 24 hours for all rHuPH20-containing formulations. The absorption rate of TCZ administered SC was estimated to be about 80% in all dose groups.

  In a cynomolgus monkey study, information was obtained regarding the toxicity of repeated doses of the TCZ SC formulation in the same species (Table 4). The TCZ plasma concentration after a single administration of a 50 mg / kg dose TCZ SC formulation was evaluated. It can be seen from the results that the TCZ maximum serum concentration (mean ± SD: 822 ± 230 μg / mL) reached 48 hours (median) after SC administration. The results of this study are available except for animals that are currently in non-treatment recovery. Tocilizumab in a recombinant hyaluronidase (rHuPH20) containing formulation administered subcutaneously to cynomolgus monkeys weekly at 100 mg / kg for 13 weeks was well tolerated systemically and locally, and there were no test item-induced findings. A non-toxic dose (NOAEL) was considered a dose level of 100 mg / kg.

Example 5
Clinical trial of SC formulation containing anti-IL-6R antibody and hyaluronidase enzyme Tocilizumab (TCZ) is a recombinant humanized IgG1 monoclonal antibody directed against soluble and membrane-bound interleukin 6 receptor (IL-6R). The hyaluronidase enzyme (rHuPH20) is used to facilitate subcutaneous (SC) formulation injection by cleaving the SC hyaluronic chain of the SC stromal matrix at the injection site. The purpose of the study was to evaluate pharmacokinetics (PK), pharmacodynamics (PD) and safety after a single escalating dose of TCZ and rHuPH20.

Materials and Methods This is a phase 1 escalating dose (TCZ162 mg alone, 162 mg, 324 mg and 648 mg TCZ + rHuPH20) study in healthy subjects. In this test, the preparations of Example 4 and Table 3 were used.

The objectives of the study are as follows:
Primary purpose:
1. To investigate the effect of rHuPH20 on exposure of various SC doses of TCZ.
Secondary purpose:
1. To investigate the safety and tolerability of a single dose of SC TCZ containing rHuPH20 in healthy individuals.
2. To investigate the PK / pharmacodynamic (PD) relationship of TCZ (with or without rHuPH20) after SC administration to healthy individuals by measuring IL-6, sIL-6R and C-reactive protein (CRP).

Overall study design This is a phase 1, single-dose, open-label, sequential, single-center study between cohorts 1 and 2 and for the remaining cohorts, from 18 to 65 years of age. The subjects were men and women with no possibility of pregnancy. Table 5 summarizes the study design.

Eligible subjects were assigned to the 1 to 4 cohorts listed in Table 6. The rHuPH20 concentration used in this study was the minipig of Example 4 above, administered SC in the presence and absence of rHuPH20 at a concentration of either 2,000 or 6,000 U / mL (nominal concentration). Derived from test data. As a result, SC-administered TCZ was absorbed faster from the rHuPH20-containing TCZ formulation. This effect on the TCZ absorption rate was comparable between both concentrations of rHuPH20. Analytical quantification of the dosing solution revealed an actual concentration of 1,356 U / mL of rHuPH20 (instead of a nominal concentration of 2,000 U / mL). Therefore, a rHuPH20 concentration of 1,500 U / mL was selected as a clinical trial plan.

  The study consisted of a screening period (from day 28 to day 2), a hospitalization period with a single dose of study drug on day 1 (from day 1 to day 2) and a follow-up period (from day 40 to day 2). 43 days).

  Eligible subjects were admitted to a clinical trial unit on day 1 and received pre-dose evaluation and treatment. Blood and urine samples were taken after a minimum of 4 hours of fasting. After a standardized light breakfast on the first morning, subjects received a TCZ SC injection in the right or left anterior thigh (midway between the anterior iliac crest and the knee head side edge). SC injection start and end times were recorded, and individual injection sites were photographed before and after injection.

  Subjects assessed pain after placement of the injection device and prior to test drug injection by a 100 mm horizontal visual analog scale (VAS) and a categorical 6-point pain self-assessment.

  The subject stayed in the unit until the 24-hour PK evaluation was completed and revisited according to instructions to receive PK and safety evaluation. To analyze serum TCZ concentrations, blood samples were collected before dosing and at 2, 8, 12, 24 and 36 hours after dosing. Additional blood samples were taken on days 3, 4, 5, 8, 11, 15, 18, 22, 29, 36 and at follow-up. Blood samples for IL-6, sIL-6R and CRP evaluation were taken at the time of PK analysis sample collection.

  Subjects revisited between days 40 and 43 to receive follow-up procedures such as physical examination, 3 serial 12 lead ECG, vital signs and clinical examination.

  Safety (clinical tests and vital signs) and PK / PD assessments were performed regularly throughout the study. Spontaneous adverse events were recorded throughout the study. The subject remained in the unit until the 24-hour PK evaluation was completed. Thereafter, subjects returned on the designated day for PK and safety assessment.

  PK and PD samples were collected thoroughly. PK and PD parameters were predicted by the non-compartment method. One-way analysis of variance was used to assess the effect of rHuPH20 on TCZ exposure. Safety and tolerability were monitored throughout the study.

Results The results of this test are shown in FIGS.

Pharmacodynamic results:
CRP: After SC TCZ administration for all cohorts, mean CRP values declined rapidly, reaching the lowest point in cohorts 1 and 2 at nominal times of 168 and 240 hours, and in cohorts 3 and 4 at 336 hours, The lowest point was generally achieved in all cohorts with a nominal time of 168 hours. Thereafter, the average CRP value increased toward the baseline value in Cohorts 1 and 2 at a nominal time of 504 hours and in Cohort 4 at a nominal time of 672 hours. Average CRP values were suppressed until 672 hours in Cohort 3, but the mean returned to baseline in the occasional follow-up sample. The average CRP values for Cohorts 1 and 2 showed similar changes from baseline, but the CRP values for Cohort 4 were delayed in time before returning to baseline. The average change from baseline values for Cohort 3 remained below baseline. A dose-dependent effect on mean CRP non-compartment parameters was observed with a dose-dependent decrease in mean AUC _0-D29 of CRP across the cohort. A dose-dependent effect of CRP T _min was also observed where a delay in mean T _min was observed with increasing dose. Please refer to FIG.
After administration of SC TCZ with or without IL-6: rHuPH20, the average IL-6 serum concentration increased rapidly in all 4 cohorts and then gradually decreased with time. In Cohorts 1 and 2, the mean IL-6 concentration reached an approximate baseline level at a nominal sample time of 504 hours, whereas in Cohort 4, the mean IL-6 serum concentration was observed on days 40-43 in the follow-up sample. The approximate baseline value has been reached. In Cohort 3, mean IL-6 values increased at a nominal time of 672 hours, but concentrations returned to approximate baseline values in irregular follow-up samples. Please refer to FIG.
After administration of SC TCZ with or without sIL-6R: rHuPH20, mean sIL-6R serum concentrations increased rapidly in all cohorts. After reaching a maximum concentration in Cohorts 1 and 2 at a nominal sample time of 240 hours, the mean sIL-6R concentration dropped to approximately baseline levels at a nominal time of 672 hours. In Cohort 4, mean sIL-6R serum concentrations decreased towards baseline values on days 40-43 in the follow-up sample after the highest concentration at a nominal time of 408 hours. In Cohort 3, the mean sIL-6R serum concentration increased rapidly after TCZ administration, continued to increase throughout all sampling points, and reached the highest observed concentration at a sample time of 672 hours. Please refer to FIG.

For non-compartment parameters of IL-6 and sIL-6R, mean AUC _0-D29 increased with increasing dose across the cohort. Mean C _max showed a similar dose-dependent increase. The observed maximum blood concentration arrival time (T _max ) increased with increasing dose.

When comparing the effect of rHuPH20 on PD response in cohort 1 (TCZ 162 mg) and cohort 2 (TCZ 162 mg / rHuPH20 1350 U), the concentration-time profile is similar in all three PD parameters (CRP, IL-6 and sIL-6R) Was. Mean PD (CRP, IL-6 and sIL-6R) AUC _0-D29 parameters are similar between cohorts 1 and 2, and the AUC _0-D29 ratio is 99 for CRP, IL-6 and sIL-6R, respectively. 0.6%, 100% and 97.4%.

Pharmacokinetic results:
The results for Cohorts 1 and 2 (with or without TCZ162 mg PH20) tend to have higher T _{max and} slightly higher exposure rates in the presence of rHuPH20 (G _max [90% confidence interval for C _max and AUC _0-inf ) ] Were 1.45 [1.24-1.70] and 1.20 [1.00-1.44]), respectively, and the TCZ serum concentration in the elimination phase could be overlaid with the two preparations. In Cohort 2 with the addition of rHuPH20, there was a clear declining trend (CV%) in the PK parameters of TCZ (with or without rHuPH20, C _max was 17.4 vs 32.4, AUC _0-inf 16.4 vs 42.0).

In cohort 3 after administration of 648 mg TCZ / PH20, the mean C _max and AUC _0-inf of TCZ were about 6.95 times and about 12.55 times higher than cohort 1 (TCZ162 mg), but the total dose was 4 Only fold higher, indicating non-dose proportionality of TCZ PK. An irregular follow-up sample of subjects in Cohort 3 (average 1909 ± 66.1 hours of actual time) revealed that TCZ serum concentrations were below the limit of quantification for all subjects, and TCZ SC single It was shown that the dose was completely eliminated.

In Cohort 4, after administration of 324 mg TCZ / PH20, the mean C _max and AUC _0-inf of TCZ were about 3.85 times and about 4.44 times higher than Cohort 1 (TCZ 162 mg), but the total dose was 2 It was only twice as expensive.

  Plasma rHuPH20 concentrations are shown to be lower than the limit of quantification for all subjects, and the use of the enzyme as a local penetration enhancer for co-administration does not result in quantifiable systemic exposure. It was.

Pharmacokinetic / pharmacodynamic relationship:
sIL-6R and TCZ: sIL-6R concentration reached Cmax after TCZ reached Cmax in all 4 cohorts, but increased TCZ concentration and produced a counterclockwise hysteresis relationship, resulting in increased sIL-6R concentration There was a delay. TCZ Cmax was achieved within 36-96 hours after TCZ administration in all cohorts, whereas sIL-6R was nominal time 240 hours in cohorts 1 and 2, nominal time 672 hours in cohort 3, and nominal time in cohort 4 Cmax was reached in 408 hours.
Similar to C-reactive protein and TCZ: sIL-6R, TCZ administration resulted in a delay in CRP reduction (ie, the CRP bottom point was reached after Cmax of TCZ). The CRP nadir was reached in cohorts 1 and 2 at nominal times of 168 and 240 hours and in cohorts 3 and 4 at 336 hours, while TCZ Cmax was observed within 36-96 hours after TCZ administration in all cohorts, A counterclockwise hysteresis relationship occurred.

Safety results:
Of the 68 reported adverse events, 61 were identified by the study investigator as possibly related to study drug treatment or remotely related. Most were injection site adverse events, which were reported only in subjects who received TCZ and rHuPH20. There were no deaths, serious adverse events, and no subjects were dropped from the study due to adverse events. There seemed to be no relationship between the number of patients who reported adverse events, the presence or absence of rHuPH20, and the TCZ dose.

  Except for the average white blood cell count and neutrophil count, the average of hematological parameters remained in the normal range throughout the study as well as the average total bilirubin, ALAT and ASAT concentrations. The mean white blood cell count and neutrophil count returned to the standard range at the end of the study. Low neutrophil counts were also the most common and characteristic laboratory abnormalities reported during the study, with a total of 30 subjects reported across all treatment groups. Infections were also reported in 8 subjects with significantly fewer neutrophil counts, but no sequelae. Most subjects' ECG measurements and vital signs were normal throughout the study. There were no clinical changes in serum IgE, IgG, IgM and IgA concentrations. Neutralizing anti-TCZ antibody was confirmed in 2 subjects receiving 648 mg TCZ / rHuPH20. None of the subjects developed neutralizing anti-rHuPH20 antibodies. Visual analog scale and patient category self-assessment indicated that all cohorts were well tolerated with SC injections.

Conclusions Pharmacokinetic and Pharmacodynamic Conclusions TCZ administration with rHuPH20 resulted in a slight increase in exposure and the geometric mean ratio (90% confidence interval) of cohort 2 (162 mg TCZ / rHuPH20) to cohort 1 (162 mg TCZ) is AUC _0-inf and C _max are 1.20 (1.00-1.44) and 1.45 (1.24-1.70), respectively, supporting the hypothesis that rHuPH20 acts as a local penetration enhancer It was done.
A trend of low PK variability in the presence of rHuPH20 was clearly observed.
As a result of the 4-fold increase in TCZ dose (648 mg TCZ / PH20) in Cohort 3, AUC _0-inf was 12.55 times and C _max was 6.96 times in 648 mg TCZ / PH20 compared to 162 mg TCZ in Cohort 1. .
As a result of the 2-fold increase in TCZ dose in Cohort 4 (324 mg TCZ / PH20), AUC _0-inf was 4.44 times and C _max was 3.85 times in 324 mg TCZ / PH20 compared to 162 mg TCZ in Cohort 1. .
SC TCZ single dose evaluated at Cohort 4 (324 mg) was mean AUC _0-inf 10800 ± 3220 μg · hr / mL, C _D29 1.6 ± 2.4 μg / mL, C _max 43.8 ± 12.4 μg / mL. mL.
SC TCZ single dose evaluated in Cohort 3 (648 mg) was mean AUC _0-inf 29900 ± 5280 μg · hr / mL, C _D29 12.6 ± 5.0 μg / mL, C _max 77.8 ± 14.5 μg / mL mL.
The effects on sIL-6R, IL-6 and CRP as PD markers were similar for SC formulations containing TCZ 162 mg, with or without rHuPH20. A dose-dependent change in the PD marker was observed with increasing TCZ / rHuPH20 from 162 mg to 648 mg.

Safety conclusions No serious adverse events were reported for the SC dose of TCZ with or without rHuPH20.
Tocilizumab treatment was associated with neutrophil loss within 2 to 5 days of treatment. Average neutrophil counts returned to baseline in a dose-dependent manner from day 15 through follow-up.
Other clinical parameters ECG, immunoglobulin concentration and vital sign recordings remained mostly within the normal range throughout the study.
Two subjects developed neutralizing anti-TCZ antibodies.
None of the subjects developed neutralizing anti-rHuPH20 antibodies.
Visual analog scale and patient category self-assessment indicated that all cohorts were well tolerated with SC injections.

Example 6
Anti-IL-6R antibody administered SQ to sJIA This example describes the use of an anti-IL-6R antibody (TCZ) administered subcutaneously for the treatment of systemic juvenile idiopathic arthritis (sJIA). A TCZ formulation (see Table 2 in Example 4) containing TCZ 180 mg / mL but no hyaluronidase is administered subcutaneously in this example.

  This is a Phase 1b open-label, multicenter, collaborative study that verifies the pharmacokinetics, pharmacodynamics, efficacy and safety of tocilizumab after subcutaneous administration to active sJIA patients. Patients treated in this study are children aged 2 to 17 years, sJIA activity has persisted for more than 6 months, and NSAIDs and corticosteroids (CS) due to lack of toxicity or efficacy Patients who had an inadequate clinical response.

  In the WA18221 study, 12 mg / kg TCZ was administered to patients with BW <30 kg, and 8 mg / kg TCZ to patients with BW ≧ 30 kg every 2 weeks for 12 weeks. PK exposure was comparable in the two weight groups (FIG. 23A). Similar sIL-6R profiles (FIG. 23B), CRP normalization patterns (FIG. 23C) and ESR profiles (FIG. 23D) were obtained in both BW groups. The equivalent PK-PD profile of the WA18221 trial resulted in efficacy and safety being acceptable over the entire weight range. 85.3% of all patients treated with TCZ met the primary endpoint of JIA ACR30 response and no fever at week 12 and were statistically significant compared to 24.3% of placebo patients. (P <0.0001). At week 12, JIA ACR 30, 50, 70, and 90 responses were 90.7%, 85.3%, 70.7%, and 37.7%, respectively, whereas in the placebo group, 24.3% and 10. It was 8%, 8.1%, 5.4%.

To further verify that the dose of WA18221 study was appropriate, the PK exposure-efficacy relationship was analyzed by PK exposure quartile. Week 12 and AUC _{Week 2} increased 2.3-fold from the first quartile (849 ± 147 μg · day / ml) to the fourth quartile (1,925 ± 187 μg · day / ml) (Table 7). ). At week 52, the Cmin of the fourth quartile (108 ± 12 μg / ml) was 3.6 times the first quartile (30 ± 16 μg / ml) (Table 7). Although this study was not enhanced to compare the effectiveness of each quartile, the percentage of patients who acquired the JIA ACR30 / 50/70/90 response is considered equivalent across the four quartiles (Table 7), suggesting that each exposure was on the plateau of the exposure-response curve. Limited data for each quartile reveals frequent and severe AEs associated with high TCZ exposure (AUC _{2 weeks} , C _max or C _min ) from the 1st to 4th quartiles No trend was shown (Table 8).

In the WA18221 study, TCZ 12 mg / kg was administered to patients <30 kg and 8 mg / kg to patients ≧ 30 kg every 2 weeks by IV infusion. Steady state C _min scatter plots (week 12) weighing 10.0-12.7 kg showed that TCZ exposure was independent of body weight (FIG. 15). Cmin predicted by the average PK model is summarized in Table 9.

  The available subcutaneous formulation is in a 1 mL prefilled syringe that delivers 0.9 mL TCZ 162 mg per injection. Therefore, the SC dose for this study is a BW wide range flat dose regimen. The initial dose for this study is selected based on modeling and simulation and is described below.

In the WA18221 study, the pharmacokinetic profile after IV administration was described by a two-compartment model with a primary elimination pathway, both saturated (Michaelis-Menten excretion) and unsaturated, from the central compartment. PK dispositon parameters were clearly characterized (total clearance (CL; L / d), central compartment distribution (Vc; L), peripheral compartment distribution (Vp; L), inter-compartment clearance ( Q; L / d), Michaelis-Menten constant (Km; mg / L) and maximum rate of saturable discharge process (Vmax; mg / d)). In the NP22623 study, TCZ 162 mg was administered to all 29 adult RA patients weekly (QW) or biweekly (Q2W) for 12 weeks. Experimental modeling of PK data for NP22623 provided subcutaneous absorption PK parameters for RA patients (absorption rate constant Ka and bioavailability F). These absorption PK parameters are similar to those of pediatric sJIA patients, and the excretion PK parameters of the WA18221 study are independent of the route of administration <30 kg and ≧ 30 kg after repeated administration to steady state. PK exposure in sJIA patients was simulated. The simulated PK profiles for IV and SC administration are shown in FIG. A PK model simulating C _min value versus body weight is shown in FIGS. The calculated PK parameters based on the simulated PK profile are summarized in Table 9.

  As expected, the IV dosing regimen showed a large variation between peak and trough concentrations during the dosing interval, but SC administration had much less variation between the peak and trough (FIGS. 14A and 14B).

Based on the PK simulation, the mean ± SD C _min (58 ± 20) obtained in sJIA patients with body weight ≧ 30 kg 162 mg QW is equivalent to 58 ± 23 in the WA18221 trial (Table 9). Individual Cmin data is also within the 90% confidence limits of the WA18221 test (FIGS. 16-18).

  Based on PK simulations, the mean ± SD Cmin for patients with body weight <30 kg 162 mg Q2W or 162 mg QW was lower (29 ± 13) or higher (100 ± 35), respectively, than the mean Cmin (58 ± 23) of the WA18221 trial. For 162 mg Q2W administration, all data are within the lowest-highest range of WA18221, but the Cmin value of 26% (10 out of 38) is lower than the 90% lower confidence limit of the WA18221 study (Figure 16). For 162 mg QW administration, 21% (8 out of 38) Cmin data is higher than the 90% upper confidence limit of the WA18221 study (Figure 17).

Based on PK model simulations, every 10 days (Q10D) of 162 mg SC injections in patients with body weight <30 kg yields mean ± SD Cmin (58 ± 22) comparable to WA18221 study data (58 ± 23). Predicted (Table 9). Out of the 90% confidence boundary, only 2 out of 38 (5%) _Cmin values (FIG. 18).

Therefore, the following treatment protocol is used:
Group 1: Patients with body weight (BW) ≧ 30 kg receive subcutaneous (SC) injection of TCZ 162 mg weekly (QW) for 14 weeks (13 doses). N = 12
Group 2: Patients with BW <30 kg receive SC injections of TCZ 162 mg every 10 days (Q10D) for 14 weeks (9 doses). N = 12

  Treatment continues for 14 weeks. During the treatment period, stable NSAIDs and MTX will continue unchanged for 14 weeks of the study. Oral steroid doses remain constant from baseline TCZ initial administration to 6 weeks. Steroid weight loss is allowed after the sixth week at the discretion of the investigator. For CS weight loss, weight loss over 20% per week is not recommended. The investigator may adjust or discontinue concurrent MTX, CS and / or NSAID treatment at any time according to standard treatment for safety reasons. Follow-up visits occur at 2, 4, and 8 weeks after the last SC administration.

Pharmacokinetic parameters include steady state C _max , C _min , T _max , T _1/2 and AUC _t .

  Pharmacodynamic parameters include sIL-6R, CRP and / or ESR concentration.

Effectiveness is assessed by:
Percentage of patients with a JIA ACR 30/50/70/90 response with or without fever at week 14; and other appropriate efficacy parameters.

  Anti-IL-6R antibody (TCZ) is considered to be effective when administered SQ weekly at a fixed dose of 162 mg, eg up to 14 weeks, in sJIA patients weighing ≧ 30 kg.

  Furthermore, anti-IL-6R antibody (TCZ) is considered to be effective when SQ is administered at a fixed dose of 162 mg every 10 days ± 1 day (Q10D) to sJIA patients with body weight <30 kg, for example, up to 14 weeks. Alternative dosing regimens include 162 mg weekly (QW) or every 2 weeks (Q2W).

Example 7
Anti-IL-6R antibody administered SQ to pcJIA Anti-IL-6R antibody (TCZ) is administered subcutaneously to polyarticular juvenile idiopathic arthritis (pcJIA) patients. A TCZ 180 mg / mL formulation without the hyaluronidase disclosed in Table 2 of Example 4 is administered here.

  This is a phase Ib open-label, multicenter, collaborative study that verifies the pharmacokinetics, pharmacodynamics, efficacy and safety of tocilizumab after subcutaneous administration to active pcJIA patients. Patients treated in this study are children aged 2 to 17 years with active arthritis in at least 5 joints (with limited movement of at least 3 joints) active pcJIA (rheumatic factor ( (RF) positive or RF negative polyarthritis subsets (including extended minority joint JIA subsets) patients with inadequate response to methotrexate (MTX) due to lack of efficacy or toxicity, NSAID, low Standard treatment with or without dose corticosteroids or combination MTX.

  Up to 30% of patients participating in this study may have previously received biological disease modifying anti-rheumatic drug (biological DMARD) treatment.

  Based on the MRA318JP Phase 3 study conducted in Japanese patients, TCZ has been approved for pcJIA treatment in Japan. The purpose of this study was to determine TCZ efficacy, safety, PK and PD after 12 weeks of TCZ 8 mg / kg infusion every 3 weeks (3 infusions). The clinical response, expressed as the probability of reaching the pcJIA50 or pcJIA70 score, was observed to be lower in lighter weight children than in heavy weight patients. After 4 weeks and 12 weeks of TCZ 8 mg / kg treatment: 88% of patients with body weight <30 kg vs. 100% of patients with body weight ≧ 30 kg reached the pcJIA50 score (FIG. 19A); 38% of patients with body weight <30 kg 80% of patients with body weight ≧ 30 kg reached the pcJIA70 score (FIG. 19B).

This significant difference in JIA ACR response rates is associated with a visual trend of low systemic exposure to TCZ (AUC _{4 weeks} ) in patients with light weight, especially those below about 30 kg. In contrast, in patients whose body weight exceeded 30 kg, exposure was considered to be more or less independent of body weight (FIG. 20A).

The TCZ PK of MRA318 TCZ was described in a two-compartment emission model with parallel first order (linear CL) and Michaelis-Menten emission (nonlinear or concentration dependent CL) kinetics. For doses of 8 mg / kg administered every 4 weeks, the contribution of non-linear CL to AUC was small and there was no related effect on _Cmax . Effect of the most prominent concentration-dependent CL components for PK of TCZ _was observed in _{C min.} C _min values were close to the average _{K M} value of the nonlinear CL component. Therefore, C _min values were in the range of concentrations small changes in serum TCZ concentration results in a relatively large change in nonlinear CL.

  Figures 24A-D show the time course PK, sIL-6R, CRP and ESR profiles during 12 weeks of treatment. The sIL-6R concentration increased over time and reached a stable state at week 12 (FIG. 24B). The CRP concentration fluctuated until the next administration and increased before the next administration (FIG. 24C). ESR decreased by week 4 and remained low after week 8 (FIG. 24D). Analysis of the PK-PD relationship showed that when serum TCZ concentrations were (1 μg / mL) or higher, CRP and ESR were low and sIL-6R saturation was high.

In the MRA318JP study, approximately 35 to 39% of patients had a TCZ Cmin of <1 μg / mL after the next infusion at weeks 4, 8, 12 after TCZ 8 mg / kg IV Q4W administration to pcJIA patients ( Table 10). Most children with MRA 318JP reached the ACR30 endpoint at week 12, but children with unmeasurable Cmin TCZ concentrations were considered to have a much lower rate of achieving JIA ACR70 than children who were measurable (25 % Vs. 73%). The majority of children whose Cmin TCZ was not measurable and did not achieve the best response were light (<30 kg).

Population PK analysis was performed based on MRA318JP data and WA19977 (117 patients) provisional PK data. In the NP22623 study, 162 mg TCZ was administered to all 29 adult RA patients for 12 weeks on QW or Q2W. Experimental modeling of NP22623 PK data yielded subcutaneous absorption PK parameters (absorption rate constant Ka and bioavailability F) for RA patients. Given that these absorbed PK parameters are similar to those of pediatric pcJIA patients and the excretion PK parameters of the WA19977 study are independent of the route of administration, pcJIA patients <30 kg after repeated administration to steady state And> 30 kg PK exposure was simulated. Simulated IV and SC dose PK profiles are shown in FIGS. 21A and 21B, respectively. The TCZ concentrations after IV and SC administration during the 4 week dosing interval at steady state were considered approximately equivalent. A model simulating TCZ exposure parameters (AUC _{4 weeks,} C _min and C _max ) is shown in Table 11. The SC dose of 162 mg Q2W for both BW <30 kg and BW ≧ 30 kg patients was considered appropriate for AUC _{4 week} production comparable to the WA19977 trial (Table 11). Therefore, the planned SC dose for all patients in Group 1 is 162 mg Q2W.

  Therefore, TCZ 162 mg is administered subcutaneously every two weeks (Q2W) to pcJIA patients (N = 24). The treatment period is 14 weeks. During the treatment period, stable NSAIDs and MTX are continued without change throughout the 14-week study. Cannot reduce corticosteroid, NSAID or methotrexate for reasons other than safety. PK, PD and efficacy parameters are evaluated at the scheduled time. Follow-up visits will be conducted 4 and 8 weeks after the last SC administration.

  Anti-IL-6R antibody (TCZ) was expected to be effective when administered to pcJIA patients at a 162 mg dose every 2 weeks (Q2W) SQ administration, eg, up to 14 weeks.

Example 8
Anti-IL-6R antibody administered to SQ in systemic sclerosis This is a phase 2/3, multicenter, randomized, double-blind, placebo controlled, 2 arm, systemic sclerosis (SSc) patient A parallel group test. A TCZ formulation containing 180 mg / mL TCZ without hyaluronidase (see Table 2 in Example 4) is administered subcutaneously to SSc patients in this study. The change from baseline at week 24 in the primary endpoint modified Rodnan skin score (mRSS) is assessed at week 24. There is a 48-week blind period followed by a 48-week open-label period.

  Patients are randomized at a 1: 1 ratio and receive either 162 mg SC TCZ weekly (QW) (Group A) or SC placebo QW (Group B) for 48 weeks. A primary analysis is performed when all patients reach week 24.

  From week 48, all patients received open-label treatment with TCZ 162 mg subcutaneous QW, and no patients receive placebo injections.

  Efficacy parameters are evaluated as described in the assessment schedule from baseline to week 96.

Register patients who meet the following target population:
Have the ability and willingness to submit written informed consent, complying with the requirements of the test protocol. Diagnosed as SSc according to the American College of Rheumatology Diagnostic Criteria (1980) Disease duration ≤ 60 months (first non-rheumatic phenomenon) Defined as the time since the appearance)
Age at baseline ≧ 18 years at screening visit ≧ 15 and ≦ 40 mRSS units Non-lesional skin in one of the following places:
Central part of the front of the thigh Lower part of the lower abdomen below the navel, excluding the area 2 inches directly from the umbilicus (when the caregiver injects the patient)
Active disease as defined in at least one of criteria A and B respectively:
Screening criteria A
≥3 increase in mRSS units at screening compared to previous visits within the past 1-6 months
1 new body region lesion with mRSS units ≧ 2 at screening compared to previous visits within the past 1-6 months ≧ 1 mRSS units at screening compared to previous visits within the past 1-6 months 2 New body area lesions Another description of worsening of skin sclerosis during screening compared to previous visits within the past 1-6 months, consistent with the progress of skin sclerosis described in the above criteria using mRSS 1 at screening Or the presence of multiple TFRs Screening criteria B
Highly sensitive C-reactive protein> 1 mg / dL
Erythrocyte sedimentation rate ≧ 28mm / hr
Platelet count (≧ 330 × 10 ³ / μL)
Treatment with oral corticosteroids (≦ 10 mg / day prednisone or equivalent) is allowed if the patient is on a stable dose regimen from ≧ 2 weeks prior to baseline.
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is allowed if the patient is on a stable dose regimen from ≧ 2 weeks prior to baseline.
Angiotensin converting enzyme inhibitors, calcium channel blockers, protein pump inhibitors and / or vasodilators are allowed if the patient is at a stable dose from ≧ 4 weeks prior to baseline.
For female patients with a potential pregnancy, the pregnancy test must be negative at screening and at the baseline visit.

Effectiveness outcome measurement The primary efficacy endpoint is the change in the modified Rodnan skin score (mRSS) from baseline to week 24. Skin hardening is assessed by palpation and scored from zero (normal) to 3 (severe skin hardening) at 17 locations. The total score is the total of 17 body areas (eg, face, hands, fingers, proximal and distal arms, chest, abdomen; proximal and distal legs, legs, legs) of an individual's 0-51 units. Skin score. This approach has been validated for SSc patients.

The secondary efficacy endpoints of this study are as follows:
Change in dysfunction index (SHAQ-DI) score from baseline to week 24 and week 48 using the scleroderma health assessment questionnaire Patients with joint involvement at baseline, week 24 to baseline And changes in 28 tender joints (TJC) at week 48 From the baseline of general assessment by doctor Changes at weeks 24 and 48 Functional evaluation of chronic disease therapy-Fatigue (FACIT)-From baseline of fatigue score Changes in Weeks 24 and 48 Change from Pruritus 5-D Itch Scale Baseline Change in Weeks 24 and 48 Change from mRSS Baseline to Week 48 Change from mRSS Baseline Percentage of patients with changes in Week 48 equal to or greater than those in Week 24

   The subcutaneously administered TCZ disclosed herein, as disclosed, improves sclerosis, improves physical function, and / or treats organ destruction in SSc patients treated compared to placebo-treated patients. Expected to delay progress. For example, the TCZ may achieve a primary efficacy endpoint (change in mRSS at week 24) and / or any one or more secondary endpoints.

Example 9
Anti-IL-6R Antibodies SQ Administered to Giant Cell Arteritis This example describes the use of anti-IL-6R antibodies (TCZ) administered subcutaneously for the treatment of giant cell arteritis (GCA). GCA patients (new-onset or refractory GCA) are treated using a TCZ formulation that does not contain the hyaluronidase described in Table 2 of Example 4 and contains TCZ 180 mg / mL.

  The treatment protocol for GCA patients is shown in FIG. The planned study is a multicenter, randomized, double-blind, placebo-controlled study of patients diagnosed with GCA. Patients can be either new onset or refractory (ie, GFCA patients who have been poorly responding to past corticosteroid (CS) treatment). The primary endpoint is that CS-free remission is maintained at 9 months. Remission is defined as normalization of the acute phase response with no signs or symptoms. Maintained is defined as no relapse after induction of remission. Patients who achieve the primary endpoint at month 9 will have remissions within 3 months and have been in remission for at least 6 months and may be able to lose CS. Secondary endpoints at 9 months include time from clinical remission to GCA disease relapse, cumulative CS dose, quality of life and changes in acute phase reactants and hemoglobin.

Two doses of subcutaneous TCZ are used:
Weekly (qw) 162 mg; and every other week (q2w) 162 mg.

Patients are randomized in a 2: 1: 1 ratio (100: 50: 50) and receive either 162 mg SC TCZ qw, 162 mg SC TCZ q2w or SC placebo for 9 months in a double-blind manner . In addition, all patients receive background CS treatment and follow a CS weight loss regimen for 6 months (see Table 12). Refractory subjects will participate in the study at a dose 10 mg greater than the previously controlled dose of the disease and will continue to attempt glucocorticoid reduction as determined by the prednisone dose at the time of study entry. Without relapse, this schedule would result in a glucocorticoid dose below 5 mg after 4 months, and no glucocorticoid would be used after 6 months.

  At 9 months, all patients can participate in study part 2 (open-label extension). Patients who meet the primary endpoint are requested to discontinue subcutaneous injections and are followed for maintenance of response. Patients who do not meet the primary endpoint have an option to escape to treatment that may include an open-label TCZ directed by the investigator. The purpose of open-label extension is to describe the long-term safety and effectiveness of the TCZ course in GCA, describe the sequelae in terms of TCZ's long-term steroid-sparing effect and CS-related adverse events, and 9 months Beyond, describe the requirements that may be needed to maintain TCZ therapy.

  The target population for this study is GCA adult patients. Newly-onset and relapsed / refractory GCA patients will be eligible.

The diagnosis of GCA follows the following criteria:
Wester Green Erythrocyte Sedimentation Rate (ESR)> 40 mm / hr Obvious cranial symptoms of GCA (new onset local headache, scalp or temporal artery tenderness, ischemia-related blindness or chewing unexplained for other reasons Mouth or jaw pain associated with
At least one of the following:
Biopsy of temporal artery showing characteristics of GCA Symptoms of rheumatic polymyalgia (PMR) defined as shoulder and / or lumbar pain associated with morning inflammatory stiffness Magnetic resonance angiography (MRA) ), Evidence of large vessel vasculitis from angiographic or cross-sectional imaging studies such as computed tomography angiography (CTA) or positron emission tomography-computed tomography angiography (PET-CTA)

New onset or refractory GCA is classified according to the following criteria.
New onset: Active GCA diagnosis within 4 weeks of baseline visit (clinical signs or symptoms and ESR> 40 mm / hr) (regardless of CS initiated or active disease activity at baseline visit)
Refractory: Active GCA diagnosed at> 4 weeks of baseline visit and within 4 weeks of baseline regardless of CS treatment (clinical signs or symptoms and ESR> 40 mm / hr)

  Subcutaneous TCZ disclosed herein effectively treats GCA, such as reducing signs and symptoms of GCA, maintaining clinical remission and / or reducing or discontinuing corticosteroids used in GCA patients Is predicted.

Claims (4)

A medicament for treating systemic sclerosis (scleroderma) or systemic scleroderma in a patient, including tocilizumab , wherein tocilizumab is administered as a fixed dose of 162 mg per dose every week or every two weeks The medicine. A medicament for treating systemic sclerosis (scleroderma) or systemic scleroderma in a patient, comprising an anti-IL-6 receptor (IL-6R) antibody, wherein the anti-IL-6R antibody is 1 Administered as a fixed dose of 162 mg per dose every week or every two weeks,
A medicament wherein the anti-IL-6R antibody has a light chain having the amino acid sequence of SEQ ID NO: 1 and a heavy chain having the amino acid sequence of SEQ ID NO: 2 . The medicament according to claim 1 or 2, which is administered subcutaneously. The medicine according to any one of claims 1 to 3, which is administered weekly.

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